Radioimaging applications of and novel formulations of teboroxime

ABSTRACT

A method for cardiac imaging is provided, including administering to an adult human subject an amount of a teboroxime species having a radioactivity of less than 5 mCi at a time of administration, and performing a SPECT imaging procedure of a cardiac region of interest (ROI) of the subject. Other embodiments are also described.

CROSS-REFERENCES TO RELATED APPLICATIONS

The present patent application claims the benefit of U.S. ProvisionalApplication 60/865,523, filed Nov. 13, 2006, entitled, “Radioimagingapplications of and novel formulations of teboroxime,” which is assignedto the assignee of the present application and is incorporated herein byreference.

The present patent application is related to:

(A) International Application PCT/IL2006/001291, filed Nov. 9, 2006;

(B) International Application PCT/IL2006/000834, filed Jul. 19, 2006;

(C) International Application PCT/IL2006/000840, filed Jul. 19, 2006;and

(D) International Application PCT/IL2006/000562, filed May 11, 2006,which is a continuation-in-part of:

(i) International Application PCT/IL2005/001215, filed Nov. 16, 2005;

(ii) International Application PCT/IL2006/000059, filed Jan. 15, 2006;

(iii) Israel Patent Application 171346, filed Oct. 10, 2005;

(iv) Israel Patent Application 172349, filed Nov. 27, 2005; and

(v) International Application PCT/IL2005/001173, filed Nov. 9, 2005,which:

(a) claims the benefit of the following US Provisional patentapplications:

-   -   60/625,971, filed Nov. 9, 2004;    -   60/628,105, filed Nov. 17, 2004;    -   60/630,561, filed Nov. 26, 2004;    -   60/632,236, filed Dec. 2, 2004;    -   60/632,515, filed Dec. 3, 2004;    -   60/635,630, filed Dec. 14, 2004;    -   60/636,088, filed Dec. 16, 2004;    -   60/640,215, filed Jan. 3, 2005;    -   60/648,385, filed Feb. 1, 2005;    -   60/648,690, filed Feb. 2, 2005;    -   60/675,892, filed Apr. 29, 2005;    -   60/691,780, filed Jun. 20, 2005;    -   60/700,318, filed Jul. 19, 2005;    -   60/700,299, filed Jul. 19, 2005;    -   60/700,317, filed Jul. 19, 2005;    -   60/700,753, filed Jul. 20, 2005;    -   60/700,752, filed Jul. 20, 2005;    -   60/702,979, filed Jul. 28, 2005;    -   60/720,034, filed Sep. 26, 2005;    -   60/720,652, filed Sep. 27, 2005; and    -   60/720,541, filed Sep. 27, 2005, and

(b) is a continuation-in-part of the following International PatentApplications:

-   -   PCT/IL2005/000572, filed Jun. 1, 2005; and    -   PCT/IL2005/000575, filed Jun. 1, 2005.

International Application PCT/IL2006/000562 also claims the benefit ofthe following US Provisional Applications:

-   -   60/750,287, filed Dec. 13, 2005;    -   60/750,334, filed Dec. 15, 2005;    -   60/750,597, filed Dec. 15, 2005;    -   60/763,458, filed Jan. 31, 2006;    -   60/741,440, filed Dec. 2, 2005; and    -   60/750,294, filed Dec. 13, 2005.

The present application additionally is related to the following USProvisional applications:

-   -   60/800,845, filed May 17, 2006;    -   60/800,846, filed May 17, 2006;    -   60/799,688, filed May 11, 2006; and    -   60/816,970, filed Jun. 28, 2006.

All of the above-mentioned applications are assigned to the assignee ofthe present application and are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates generally to radiological imagingtechniques and radiopharmaceutical agents, and specifically to apparatusand methods for performing imaging procedures using teboroxime Tc-99m,and novel formulations of teboroxime Tc-99m.

BACKGROUND OF THE INVENTION

[Bis[1,2-cyclohexanedionedioxamato(1-)-O]-[1,2-cyclohexanedioneioximato(2-)-O]methylborato(2-)-N,N′,N″,N′″,N″″,N′″″]-chlorotechnetium-99m(hereinbelow, “Tc-99m teboroxime” or just “teboroxime”) is aradiopharmaceutical agent indicated for cardiac imaging, particularlyfor myocardial perfusion imaging to distinguish normal from abnormalmyocardium in patients with suspected coronary artery disease (CAD)using rest and stress techniques. Teboroxime, which a member of a classof radiopharmaceuticals known as boronic acid adducts of technetiumdioxime (“BATO” compounds), is a neutral, lipophilic agent labeled withtechnetium Tc-99m that is used for myocardial perfusion imaging (Narra[1989], all references cited hereinbelow). Teboroxime has the advantageof using Tc-99m (6 hours half-life and 140 keV photon energy) as theimaging radionuclide, while maintaining linear uptake with flow at highflow rates (Chiao [1994]). Its very high extraction (Leppo [1990])potentially makes it an excellent perfusion agent for detecting mild tomoderate severity coronary disease with high sensitivity andspecificity. The rapid clearance characteristics of teboroximepotentially allows serial testing (rest, peak stress, and washout) in acontracted time frame, which also makes teboroxime valuable for use inclinical imaging.

Teboroxime is described in U.S. Pat. No. 4,705,849 to Nunn et al., whichis incorporated herein by reference. Technetium-99m as a pertechnetateion containing salt is combined with a source of anion, a boronic acidderivative having the formula

or a pharmaceutically acceptable salt thereof, wherein R₇ is hydrogen,alkyl or aryl, and a dioxime having the formula

or a pharmaceutically acceptable salt thereof. The size of the host, andthe imaging system used, are described as determining the quantity ofradioactivity needed to produce diagnostic images. For a human host, thequantity of radioactivity injected normally ranges from about 5 to 20millicuries (mCi) of technetium-99m.

U.S. Pat. No. 6,056,941 to Schramm et al., which is incorporated hereinby reference, describes a kit for forming teboroxime in situ in thepresence of hydroxypropyl gamma cyclodextrin to maintain the solutionfree of particulate matter originating from the formulation. Theteboroxime formed has a radiation dose of 10 to 100 mCi.

Reference is made to FIG. 1, which is a graph from Case et al. (2001),cited hereinbelow, which shows the average teboroxime uptake as afunction of time post-injection for the heart, liver, and background.One of the known drawbacks of teboroxime is that once it returns to theblood, it is readily taken up by the liver and other sub-diaphragmaticstructures which potentially “obscure” the inferior wall of the heart.Thus, there is a short window of opportunity for imaging thepost-injection perfusion pattern during which there is a peak heart tobackground ratio. Although teboroxime was approved for marketing by theU.S. Food and Drug Administration in 1991, it was subsequentlydiscontinued by the manufacturer. Teboroxime “was not marketed becauseof limitations of hardware (nuclear cameras) and software of that era.Recently, Bracco Diagnostics, Inc. acquired the product and is planningto reintroduce it providing that an imaging protocol that capitalizes onits unique kinetics and software for processing, display andquantitation can be developed” (Case et al. [2001]).

Stewart R E et al., in “Myocardial clearance kinetics oftechnetium-99m-SQ30217: a marker of regional myocardial blood flow,” JNucl Med 31:1183-1190 (1990), which is incorporated herein by reference,describe a study that evaluated the myocardial tracer kinetics oftechnetium-99m-SQ30217 (teboroxime). The authors note that “Currentlyemployed single- and dual-head tomography does not provide the necessarytemporal resolution to delineate the kinetics of SQ30217 in the humanheart. The newer multi-head SPECT systems may provide sufficienttemporal resolution for the clinical application of ^(99m)Tc-SQ30217(18)” (p. 1189).

Chua T et al., in “Technetium-99m teboroxime regional myocardial washoutin subjects with an without coronary artery disease,” Am J Cardiol72:728-734 (1993), which is incorporated herein by reference, describe astudy designed “to test the hypothesis that regional myocardial washoutof technetium-99m teboroxime is slowed in the presence of coronarystenosis” (abstract). Regional variability in washout rates wereobserved, “with the anterior and high lateral regions having the slowestwashout, and the inferior wall the highest” (p. 732). “A possibleexplanation for this regional variation in washout rates is the effectof hepatic teboroxime uptake on the measured activity in the inferiorwall. Liver uptake of teboroxime is avid, peaking 6 minutes afterinjection of teboroxime, and may interfere with visual assessment of theinferior wall” (p. 732).

Case T et al., in “Rapid back to back adenosine stress/resttechnetium-99m teboroxime myocardial perfusion SPECT using atriple-detector camera,” J Nucl Med 34:1485-1493 (1993), which isincorporated herein by reference, describe imaging parameters and theclinical efficacy of a rapid back to back adenosine stress/restteboroxime myocardial perfusion SPECT protocol using a triple-detectorcamera. The authors note that “The rapid myocardial washout ofteboroxime coupled with its intense late hepatic uptake necessitatesthat imaging be completed more quickly than with ²⁰¹Tl or ^(99m)Tcsestamibi” (p. 1485). The triple-headed camera used was able to produce“2-3 minute and 2-5 minute anterior view adenosine teboroxime (20-25mCi) images containing 8,000-9,000 and 12,000-15,000 myocardial counts,respectively. The authors conclude, “Thus, despite the use of atriple-head detector camera and continuous acquisition, teboroximestudies with this fast protocol result in relatively low-count images”(p. 1490).

Feng B et al., in “Simultaneous assessment of cardiac perfusion andfunction using 5-dimensional imaging with Tc-99m teboroxime,” J NuclCardiol 13(3):354-61 (2006), which is incorporated herein by reference,investigated the feasibility of simultaneously imaging myocardialischemia and transient post-stress akinesis using gated-dynamic SPECT. Agated-dynamic mathematical cardiac torso (MCAT) phantom was developed tomodel both teboroxime kinetics and cardiac regional wall motion. Alesion was simulated as having delayed post-stress teboroxime washouttogether with a transient post-stress wall motion abnormality. Gatedprojection data were created to represent a 3-headed SPECT systemundergoing a total rotation of 480 degrees. The dynamicexpectation-maximization reconstruction algorithm with post-smoothingacross gating intervals by Wiener filtering, and the ordered-subsetexpectation maximization reconstruction algorithm with 3-point smoothingacross gating intervals were compared. Compared with the ordered-subsetexpectation maximization with 3-point smoothing, the dynamicexpectation-maximization algorithm with Wiener filtering was able toproduce visually higher-quality images and more accurate leftventricular ejection fraction estimates. The authors conclude that, fromsimulation, changing cardiac function and tracer localization possiblycan be assessed by using a gated-dynamic acquisition protocol combinedwith a 5-dimensional reconstruction strategy.

Sitek A et al., in “Removal of liver activity contamination inteboroxime dynamic cardiac SPECT imaging with the use of factoranalysis,” J Nucl Cardiol 9(2):197-205 (2002), which is incorporatedherein by reference, write, “One of the major problems associated withtechnetium 99m teboroxime cardiac imaging is the high concentration ofactivity in the liver. In some cases it is impossible to diagnosedefects on the inferior wall because of the finite resolution andscatter that cause images of the inferior wall and the liver tooverlap.” The least-squares factor analysis of dynamic structuresmethod, with correction for non-unique solutions, was used to remove theliver activity from the image. The method was applied to dynamicallyacquired Tc-99m teboroxime data. The liver activity removal method wastested through use of computer simulations and tomographically acquiredcanine and patient cardiac studies. The authors report that in allstudies the least-squares factor analysis of dynamic structures methodwas able to extract the liver activity from the series of dynamicimages, thereby making it possible to remove it quantitatively from theentire series. The method is described as being used successfully toremove the liver activity that partially overlapped the inferior wall innormal hearts. The method tends to increase the contrast between defectsand normal myocardial tissue in abnormal hearts. The authors concludethat the method presented can be used to assist in diagnosis of cardiacdisease when dynamically acquired teboroxime data are used. Because thecontrast between the defect and normal myocardial tissue can be changed,the processed image cannot be used by itself to make an accuratediagnosis. However, with the liver activity removed, the image providesadditional information that is described as being very useful in theimaging of patients whose liver activity overlaps the inferior heartwall.

The following references regarding teboroxime, all of which areincorporated herein by reference, may be of interest:

-   “CARDIOTEC® Kit for the Preparation of Technetium Tc 99m Teboroxime    For Diagnostic Use” package insert, Bracco Diagnostics (July 2003)-   Bontemps L et al., “Technetium-99m teboroxime scintigraphy. Clinical    experience in patients referred for myocardial perfusion    evaluation,” Eur J Nucl Med 18(9):732-9 (1991)-   Chua et al. in J Nucl Med in 1982-   Chiao P C et al., “Compartmental analysis of technetium    99m-teboroxime kinetics employing fast dynamic SPECT at stress and    rest,” J Nucl Med 35:1265-73 (1994)-   Meerdink D J et al., “Experimental studies of the physiologic    properties of technetium-99m agents: myocardial transport of    perfusion imaging agents,” Am J Cardiol 66:9 E-15E (1990)-   Leppo J A et al., “Comparative myocardial extraction of two    technetium-labeled BATO derivatives (SQ30217, SQ32014) and    thallium,” J Nucl Med 31:67-74 (1990)-   Narra R K et al., “A neutral technetium-99m complex for myocardial    imaging,” J Nucl Med 30:1830-1837 (1989)-   Garcia E V et al, “Accuracy of dynamic SPECT acquisition for Tc-99m    teboroxime myocardial perfusion imaging: preliminary results,”    American College of Cardiology 51st Annual Scientific Session,    Atlanta, Ga. (Mar. 17-20, 2002)-   Case J A et al., in “Myocardial kinetics of technetium-99m    teboroxime: a new radiopharmaceutical for assessing myocardial    perfusion” (2001)-   Case J A et al., “Reducing impact of changing liver concentration in    Tc-99m-teboroxime imaging using dynamic SPECT,” Cardiovascular    Imaging Technologies, Kansas City, Mo. and Emory University,    Atlanta, Ga., Annual Meeting of the Society of Nuclear Medicine, Los    Angeles (2002)-   Reutter B W et al., “Effects of temporal modelling on the    statistical uncertainty of spatiotemporal distributions estimated    directly from dynamic SPECT projections,” Phys Med Biol    47(15):2673-83 (2002)-   Reutter B W et al., “Accuracy and precision of compartmental model    parameters obtained from directly estimated dynamic SPECT    time-activity curves,” 2002 IEEE Nuclear Science Symposium and    Medical Imaging Conference Records, pp. 1584-1588 (preprint) (2002)-   Sitek A et al., “Correction for ambiguous solutions in factor    analysis using a penalized least squares objective,” IEEE Trans Med    Imaging 21(3):216-25 (2002)-   Yang D J et al., “Imaging with 99 mTc ECDG targeted at the    multifunctional glucose transport system: feasibility study with    rodents,” Radiology 226:465-473 (2003)-   El Fakhri G et al., “Quantitative dynamic cardiac ⁸²Rb PET using    generalized factor and compartment analyses,” J Nucl Med    46:1264-1271 (2005)-   Dilsizian V et al., “Metabolic imaging with    beta-methyl-p-[(123)I]-iodophenyl-pentadecanoic acid identifies    ischemic memory after demand ischemia,” Circulation    112(14):2169-74 (2005) Epub 2005 Sep. 26-   Gullberg G T et al., “Chapter 8: Dynamic Cardiac Single-Photon    Emission Computed Tomography Using Fast Data Acquisition Systems,”    in Zaret B L et al., Clinical Nuclear Cardiology: State of the Art    and Future Directions (Elsevier Mosby, 3rd edition, 2004)-   PCT Publication WO 06/051531 to Rousso et al., which is assigned to    the assignee of the present application and is incorporated herein    by reference, describes radioimaging methods, devices and    radiopharmaceuticals. The publication describes several teboroxime    preparation and imaging protocols.

U.S. Pat. No. 6,242,743 to DeVito et al., which is incorporated hereinby reference, describes a tomographic imaging system which imagesionizing radiation such as gamma rays or x-rays. The system is describedas being capable of producing tomographic images without requiring anorbiting motion of the detector(s) or collimator(s) around the object ofinterest, and of observing the object of interest from sufficiently manydirections to allow multiple time-sequenced tomographic images to beproduced. The system consists of a plurality of detector modules whichare distributed about or around the object of interest and which fullyor partially encircle it. The detector modules are positioned close tothe object of interest thereby improving spatial resolution and imagequality. The plurality of detectors view a portion of the patient orobject of interest simultaneously from a plurality of positions. Theseattributes are achieved by configuring small modular radiation detectorwith high-resolution collimators in a combination ofapplication-specific acquisition geometries and non-orbital detectormodule motion sequences composed of tilting, swiveling and translatingmotions, and combinations of such motions. Various kinds of modulegeometry and module or collimator motion sequences are possible. Thegeometric configurations may be fixed or variable during the acquisitionor between acquisition intervals.

The following patents and patent application publications, whichdescribe gamma cameras and imaging processing techniques, and which areincorporated herein by reference, may be of interest:

US Patent Application Publication 2005/0205792 to Rousso et al.

PCT Publication WO 05/118659 to Dichterman et al.

PCT Publication WO 05/119025 to Nagler et al.

US Patent Application Publication 2004/0204646 to Nagler et al.

PCT Publication WO 06/054296 to Dickman

PCT Publication WO 06/051531 to Rousso et al.

PCT Publication WO 04/042546 to Kimchy et al.

US Patent Application Publication 2004/0054248 to Kimchy et al.

US Patent Application Publication 2004/0015075 to Kimchy et al.

US Patent Application Publication 2004/0054278 to Kimchy et al.

US Patent Application Publication 2005/0266074 to Zilberstein et al.

U.S. Pat. Nos. 5,939,724, 5,587,585, and 5,365,069 to Eisen et al.

U.S. Pat. No. 6,943,355 to Shwartz et al.

U.S. Pat. No. 5,757,006 to DeVito et al.

U.S. Pat. No. 6,137,109 to Hayes

U.S. Pat. No. 6,388,258 to Berlad et al.

U.S. Pat. No. 6,429,431 to Wilk

U.S. Pat. No. 6,838,672 to Wagenaar et al.

U.S. Pat. Nos. 6,740,882, 6,545,280, 6,229,145, 5,519,221, 5,252,830,and 6,628,984 to Weinberg

U.S. Pat. No. 6,713,766 to Garrard et al.

U.S. Pat. No. 6,765,981 to Heumann

U.S. Pat. No. 6,664,542 to Ye et al.

U.S. Pat. No. 6,080,984 to Friesenhahn

U.S. Pat. No. 5,818,050 to Dilmanian et al.

U.S. Pat. No. 6,728,583 to Hallett

U.S. Pat. No. 5,481,115 to Hsieh et al.

U.S. Pat. No. 6,723,988 to Wainer

U.S. Pat. No. 6,940,070 to Turner

U.S. Pat. No. 6,635,879 to limbo et al.

U.S. Pat. No. 6,353,227 to Boxen

U.S. Pat. No. 6,184,530 to Hines et al.

US Patent Application Publication 2005/0145797 to Oaknin et al.

US Patent Application Publication 2004/0251419 to Nelson et al.

US Patent Application Publication 2003/0001098 to Stoddart et al.

PCT Publication WO 98/16852 to DeVito et al.

PCT Publication WO 05/059840 to Nielsen et al.

U.S. Pat. No. 5,813,985 to Carroll

The following articles, all of which are incorporated herein byreference, may be of interest:

-   Van Den Bossche B et al., “Receptor Imaging in Oncology by Means of    Nuclear Medicine Current Status,” Journal of Clinical Oncology    22(17):3593-3607 (2004)-   Yao D et al., “The utility of monoclonal antibodies in the imaging    of prostate cancer,” Semin Urol Oncol 20(3):211-8 (2002)-   van der Laken C J et al., “Technetium-99m-labeled chemotactic    peptides in acute infection and sterile inflammation,” J Nucl Med    38(8):1310-5 (1997)-   Babich J W et al., “Localization of radiolabeled chemotactic peptide    at focal sites of Escherichia coli infection in rabbits: evidence    for a receptor-specific mechanism,” J Nucl Med 38(8):1316-22 (1997)-   Rao P S et al., “99 mTc-peptide-peptide nucleic acid probes for    imaging oncogene mRNAs in tumours,” Nuclear Medicine Communications    24(8):857-863 (2003)-   Fischman A J et al., “Infection imaging with technetium-99m-labeled    chemotactic peptide analogs,” Semin Nucl Med 24(2):154-68 (1994)-   Massoud T F et al., “Molecular imaging in living subjects: seeing    fundamental biological processes in a new light,” Genes &    Development 17:545-580 (2003)-   Gambhir S S, “Molecular imaging of cancer with positron emission    tomography,” Nature Reviews 2:683-693 (2002)

SUMMARY OF THE INVENTION

Embodiments of the present invention provide novel BATO-based, includingteboroxime-based, kits and labeled radiopharmaceutical agents, imagingprotocols, a SPECT imaging system for performing cardiac imaging, and anend-to-end automated system for enabling the protocols and imaging.

In some embodiments of the present invention, the SPECT imaging systemproduces a “clinically-valuable image,” as defined hereinbelow, of acardiac region of interest (ROI) upon administration of teboroxime at adose of about 15 to about 50 mCi, such as about 15 to about 35 mCi. Theinventors believe that conventional SPECT imaging systems have not beenable to produce such clinically-valuable images, and that such failurewas a primary reason why the manufacturer of teboroxime voluntarilywithdrew the drug from the market in the United States, and has yet toreintroduce it despite development efforts to produceclinically-valuable images. Evidence is presented hereinbelowdemonstrating that the imaging system of the present invention iscapable of producing such clinically-valuable images. In summary, suchevidence demonstrates that the SPECT imaging system of embodiments ofthe present invention is able to obtain at least 5 times the sensitivityof conventional SPECT imaging systems, such as at least 7 times or 10times the sensitivity of conventional SPECT imaging systems. Thisgreater sensitivity enables the generation of clinically-valuable imagesprior to contamination of the liver by the teboroxime, which occurs atabout 5 minutes after injection.

In some embodiments of the present invention, the SPECT imaging systemperforms a complete teboroxime-based myocardial perfusion scan inbetween about 2 and about 3 minutes, which is quickly enough to capturethe rapid kinetics of teboroxime prior to contamination by liveremissions. For some applications, the system performs dynamic imaginghaving a time resolution of as fast as 5 seconds per full scan of theheart. Such dynamic imaging enables the monitoring of the wash-in andwashout kinetics of teboroxime. The dynamic data is analyzed usingkinetic perfusion models specific to teboroxime to calculate myocardialblood flow and coronary flow reserve (CFR).

In some embodiments of the present invention, a kit for the preparationor a container containing a dose of a radiolabeled radiopharmaceuticalagent comprises a boronic acid adduct of 99m-technetium dioxime(99m-BATO), such as teboroxime, having a radioactivity of less than 5mCi, such as less than or equal to 4.5 mCi, less than or equal to 4 mCi,or less than or equal to 3 mCi, e.g., between about 2 and about 3 mCi.The SPECT imaging system is able to produce clinically-valuable imagesusing this kit or dose. To the knowledge of the inventors, prior artteboroxime kits, either marketed or described in the patent and medicalliterature, contain at least 5 mCi technetium Tc-99, because it was notcontemplated that lower doses could produce clinically-valuable imagesin adult human subjects.

In some embodiments of the present invention, ultra-fast rest/stressprotocols are provided that use teboroxime for rest and/or stressimaging. Some of these protocols provide (a) a rest administration ofteboroxime having a dose of between about 8 and about 12 mCi, and restimaging having a duration of about 3 minutes, followed by (b) a stressadministration of teboroxime having a dose of between about 20 and about40 mCi, e.g., between about 25 and about 35 mCi, and stress imaginghaving a duration of about 4 minutes. Alternatively, the protocolsubstitutes thallium having a radioactivity of between about 3 and about5 mCi, between about 1 and about 5 mCi, or less than about 1 mCi, forone of the rest or stress imaging.

In some embodiments of the present invention, the administration andimage capture phases of the protocols described herein are performed ina single session while the patient remains continuously under the cameraof the imaging system. The patient's remaining in place is generallymore convenient and comfortable for the patient, and more efficient forthe imaging facility. Many of the protocols described herein areperformed with a total duration of less than 30 minutes, such as lessthan 20 minutes, or less than 15 minutes. Typically, although notnecessarily, the protocols described herein are performed using a kitthat provides the radiopharmaceutical agents and other agents, and usingan integrated automated administration and imaging system, such asdescribed herein.

In some embodiments of the present invention, protocols are providedthat use teboroxime in combination with another radiopharmaceuticalagent, such as I-123 BMIPP or Tc-99m ECDG. For some applications, theseprotocols include a dual-isotope teboroxime stress/I-123 BMIPP protocol,for a combined perfusion and fatty acid imaging study. This protocolprovides stress imaging using teboroxime having a dose of between about20 and about 40 mCi, e.g., between about 25 and about 35 mCi, followedby post-stress imaging using BMIPP having a dose of between about 3 andabout 5 mCi. These protocols also include a dual-isotopesimultaneous-imaging teboroxime rest/I-123 BMIPP protocol, for acombined perfusion and fatty acid imaging study. These protocols furtherinclude a dual-isotope teboroxime rest/Tc-99m ECDG stress protocol for acombined perfusion and glucose imaging study (either static or dynamic).

For other applications, these teboroxime combination protocols useteboroxime and another Tc-99m-based radiopharmaceutical agent, such as^(99m)Tc-sestamibi or ^(99m)Tc-tetrofosmin. Such other Tc-99-m-basedradiopharmaceutical agents typically remain longer in the heart thandoes teboroxime. Typically, these protocols comprise first administeringteboroxime and performing imaging, followed by administering the otherTc-99m-based radiopharmaceutical agent and performing imaging. For someapplications, the first administration is performed under stress(physical or pharmacological), and the second administration isperformed at rest, while for other applications, the firstadministration is performed at rest, and the second administration isperformed under stress.

Alternatively, these protocols comprise first administering the otherTc-99-m-based radiopharmaceutical agent, and beginning the imaging ofthe other agent. Before this imaging is completed, the teboroxime isadministered and imaged, and the imaging continues until the teboroximehas substantially washed out of the heart, such that the other agentremains and imaging thereof is completed. The interference of theemissions from the other agent is estimated based on the detected levelsof emission before administration of the teboroxime and after itswash-out, and these emissions are subtracted out of the counts obtainedduring the imaging of the teboroxime. For example, the other agent maycomprise ^(99m)Tc-sestamibi, which may be administered under stress,such as before the patient is positioned at the imaging system.

Further alternatively, the other Tc-99-m-based radiopharmaceutical agentis administered first, such as under stress, and subsequently theteboroxime is administered. Imaging of the teboroxime is performedfirst, and after the teboroxime has substantially washed out of theheart, imaging of the other agent is performed.

In some embodiments of the present invention, the kit comprisesadditional components, which are injected independently or together withother components of the kit, or, alternatively, are pre-mixed with atleast one other component of the kit. For example, these othercomponents may comprise: (a) saline for performing a “flush”; (b)BMIPP-I123 for imaging of fatty-acid metabolism; (c) F18-labeled FDG forimaging glucose metabolism; and/or (d) Tc-99m-labeled glucose (e.g.,Tc-99m-2-deoxy-d-glucose) for imaging glucose metabolism. In someembodiments of the present invention, protocols described herein includeadministering and/or imaging at least one of these additionalcomponents, either separately from or simultaneously with other steps ofthe protocols.

In some embodiments of the present invention, a teboroxime protocolprovides a dynamic study for performing blood flow measurements andcalculation of coronary flow reserve (CFR). The protocol begins with anestimation of an input function, by sampling the myocardium inapproximately 5-second intervals during a first, low-resolution restphase having a duration of about 0.5 minutes. Once the tracer begins todiffuse into the myocardium, the sampling time of the myocardium isincreased, typically to approximately 30-second intervals. The systemanalyzes these dynamic sequences using a compartmental analysisapproach. Typically, this rest phase of the protocol is followed by astress phase, in which the low- and high-resolution imaging arerepeated.

In some embodiments of the present invention, the SPECT imaging systemcomprises a plurality of detector assemblies, each of which comprises adetector coupled to an angular orientator. Each of the detectorscomprises a plurality of gamma ray sensors and at least one collimator.A control unit drives, typically separately, each of the orientators toorient its respective detector in a plurality of rotational orientationswith respect to a region of interest (ROD of a subject. The control unitproduces an image, typically a SPECT image, from a plurality ofradiation acquisitions acquired with the detectors in different relativeorientations. For some applications, the imaging system utilizestechniques described in the above-mentioned PCT Publications WO06/051531 and/or WO 05/119025, and/or in the other patent applicationsand/or patent application publications incorporated herein by reference.

The SPECT imaging system is generally at least 10 times more sensitivethan conventional SPECT imaging systems, and thus enables the generationof clinically-valuable images using the techniques and protocolsdescribed herein.

In some embodiments of the present invention, an end-to-end automatedsystem for medical imaging comprises a plurality of integrated elementsthat are configured to electronically exchange information among oneanother. In addition to the imaging system described hereinabove, theelements include an automated radiopharmaceutical dispensing system, aportable information-bearing radiopharmaceutical agent container, aportable patient-specific data carrier, and an automated administrationsystem. Typically, a data carrier is physically coupled to container.The systems perform their respective automated functions at least inpart responsively to the exchanged information. The elements typicallyauthenticate one another via the exchanged information, in order toensure that only authorized elements participate in the system, and thatonly authorized and appropriate functions are performed.

In some embodiments of the present invention, the automatedradiopharmaceutical dispensing system comprises an information managerthat is configured to receive radiopharmaceutical information regardinga labeled radiopharmaceutical agent and patient information regarding apatient. Responsively to the information, the dispensing systemautomatically dispenses a dose of the labeled radiopharmaceutical agentto an agent container, and stores the radiopharmaceutical informationand at least a portion of the patient information in a data carrierassociated with the container. For some applications, theradiopharmaceutical information is selected from the group consistingof: imaging protocol information for use with the labeledradiopharmaceutical agent, such as a SPECT imaging protocol; at leastone kinetic parameter useful for performing a dynamic SPECT imagingprocedure using the at least one labeled radiopharmaceutical agent; andauthenticatable information regarding a commercial license for use of aSPECT imaging protocol with the at least one labeled radiopharmaceuticalagent.

In some embodiments of the present invention, the dispensing system isconfigured to receive a mother vial containing a labeledradiopharmaceutical agent in a quantity sufficient for preparation of aplurality of doses of the labeled radiopharmaceutical agent. Associatedwith the mother vial is a data carrier containing information regardingthe labeled radiopharmaceutical agent, such as the formulation,radioactivity information, and protocol information. The informationmanager of the dispensing system receives at least a portion of thelabeled radiopharmaceutical agent information from the data carrier.

There is therefore provided, in accordance with an embodiment of thepresent invention, a method for cardiac imaging, including:

administering to an adult human subject an amount of a^(99m)Tc-containing species having a radioactivity of less than 5 mCi ata time of administration; and

performing a SPECT imaging procedure of a cardiac region of interest(ROI) of the subject, wherein said ^(99m)Tc-containing species has theformula ^(99m)TcX(Y)₃Z, wherein:

X is an anion;

each Y, which is independently chosen, is a vicinal dioxime having theformula HON═C(R₁)C(R₂)═NOH or a pharmaceutically acceptable saltthereof, wherein R₁ and R₂ are each independently hydrogen, halogen,alkyl, aryl, amino or a 5 or 6-membered nitrogen or oxygen containingheterocycle, or together R₁ and R₂ are —(CR₈CR₉)_(n)— wherein n is 3, 4,5 or 6 and R₈ and R₉ are each independently hydrogen or alkyl; and

Z is a boron derivative of the formula B—R₃

wherein R₃ is hydroxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy,carboxyalkyl, carboxyalkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl,alkoxyalkenyl, haloalkyl, haloalkenyl, aryl, arylalkyl or (R₄R₅N)-alkyland R₄ and R₅ are each independently hydrogen, alkyl, or arylalkyl, orR₄ and R₅ when taken together with the nitrogen atom to which they areattached form a 5 or 6-membered nitrogen containing heterocycle.

The following embodiments of the ^(99m)Tc-containing species having theformula ^(99m)TcX(Y)₃Z are generally applicable to embodiments of^(99m)Tc-containing species having the formula ^(99m)TcX(Y)₃Z describedthroughout the present patent application.

In an embodiment, said Tc-99m-containing species has the structure:

In an embodiment, said ^(99m)Tc-containing species has the structure:

In an embodiment, the method includes mixing:

(i) a source of anion;

(ii) a boronic acid derivative, or compounds which can react in situ toform a boronic acid derivative, having the formula R₃B(OR₇)(OR₇) or apharmaceutically acceptable salt thereof, wherein R₃ is hydroxy, alkyl,alkenyl, cycloalkyl, cycloalkenyl, alkoxy, carboxyalkyl, carboxyalkenyl,hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, alkoxy-alkenyl, haloalkyl,haloalkenyl, aryl, arylalkyl, or R₄R₅N-alkyl and R₄ and R₅ are eachindependently hydrogen, alkyl, or arylalkyl, or R₄ and R₅ when takentogether with nitrogen atom to which they are attached form a 5 or6-membered nitrogen containing heterocycle, and each R₇ is independentlyselected from hydrogen, alkyl and aryl;

(iii) at least one dioxime having the formula HON═C(R₁)C(R₂)═NOH or apharmaceutically acceptable salt thereof, wherein R₁ and R₂ are eachindependently hydrogen, halogen, alkyl, aryl, amino or a 5 or 6-memberednitrogen or oxygen containing heterocycle, or together R₁ and R₂ are—(CR₈R₉)_(n)— wherein n is 3, 4, 5 or 6 and R₈ and R₉ are eachindependently hydrogen or alkyl;

(iv) a reducing agent; and

(v) a source of ^(99m)Tc;

whereby to obtain the ^(99m)Tc-containing species,

wherein administering includes administering the ^(99m)Tc-containingspecies thus obtained.

For some applications, the method further includes heating the mixedingredients for a time and at a temperature sufficient to form said^(99m)Tc-containing species. For example, said mixing may furtherinclude mixing one or more complexing agents. For some applications,said complexing agent is selected from the group consisting ofdiethylenetriamine-pentaacetic acid, ethylene glycol-bis(β-aminoethylether)-N,N′-tetraacetic acid, ethylenediamine tetraacetic acid, citricacid, tartaric acid and malonic acid.

For some applications, said mixing further includes mixing at least onecatalyst. For example, said at least one catalyst may include anα-hydroxycarboxylic acid, which may be selected from the groupconsisting of citric acid, tartaric acid, and malonic acid.

In an embodiment, X is chloride, bromide or iodide. In an embodiment, Xis chloride.

In an embodiment, Y is selected from:

-   -   dimethyl glyoxime, 1,2-cyclohexanedione dioxime, 1,2-ethanedione        dioxime, α-furyldioxime, 1,2-cyclopentanedione dioxime, and        3-methyl-1,2-cyclopentanedione dioxime.    -   dimethyl glyoxime.    -   1,2-cyclohexanedione dioxime.    -   1,2-ethanedione dioxime.    -   α-furyldioxime.

In an embodiment, Z is B-alkyl, e.g., B-methyl, B-alkoxy, B-benzyl, orB-cycloalkyl.

In an embodiment, the ^(99m)Tc-containing species is selected from:

-   -   ^(99m)Tc (chlorine) (1,2-cyclohexanedione dioxime)₃ methyl        boron.    -   ^(99m)Tc (chlorine) (dimethyl glyoxime)₃ 1-methylpropyl boron.    -   ^(99m)Tc (chlorine) (dimethyl glyoxime)₃ 4-methylphenyl boron.    -   ^(99m)Tc (chlorine) (dimethyl glyoxime)₃ cyclopentyl boron.    -   ^(99m)Tc (chlorine) (1,2-cyclohexanedione dioxime)₃ ethyl boron.    -   ^(99m)Tc (chlorine) (dimethyl glyoxime)₃ 4-(t-butyl)phenyl        boron.    -   ^(99m)Tc (chlorine) (dimethyl glyoxime)₃ 2-methyl-1-propyl        boron.    -   ^(99m)Tc (chlorine) (1,2-cyclohexanedione dioxime)₃ hydroxy        boron.

For some applications, said source of anion is NaCl, said boronic acidderivative is methyl boronic acid; said dioxime is cyclohexanedionedioxime, and said reducing agent is stannous chloride. For someapplications, said mixing further includes mixing citric acid andpentetic acid with said source of anion, said boronic acid derivative,said dioxime and said reducing agent. For some applications, said mixingfurther includes mixing hydroxypropyl gamma cyclodextrin with saidsource of anion, said boronic acid derivative, said dioxime and saidreducing agent.

In an embodiment, performing the SPECT imaging procedure includesperforming a dynamic SPECT imaging procedure.

In an embodiment, administering the ^(99m)Tc-containing species includesdispensing the ^(99m)Tc-containing species with an initial radioactivitygreater than the radioactivity at the time of administration, and suchinitial radioactivity is calculated based at least in part on ahalf-life of the ^(99m)Tc and an estimate of the time of administration,to provide the radioactivity at the time of administration.

In an embodiment, performing the SPECT imaging procedure includesacquiring at least one in 5000 photons emitted from the ROI during theSPECT imaging procedure, such as at least one in 2000 photons emittedfrom the ROI during the SPECT imaging procedure.

In an embodiment, performing the SPECT imaging procedure includesperforming the SPECT imaging procedure with an image acquisition periodhaving a duration of no more than 15 minutes, such as no more than 10minutes, 8 minutes, 5 minutes, 3 minutes, 2 minutes, 1 minute, 40seconds, 30 seconds, 20 seconds, 10 seconds, or 5 seconds.

In an embodiment, acquiring the image includes acquiring, during theimage acquisition period, at least 200,000 photons emitted from aportion of the ROI, which portion has a volume of no more than 500 cc,such as at least 1,000,000 photons during the image acquisition periodfrom the portion of the ROI having the volume of no more than 200 cc.

In an embodiment, performing the SPECT imaging procedure includesgenerating an image having a resolution of at least 7×7×7 mm. For someapplications, the ^(99m)Tc-containing species as distributed within theROI has a range of emission-intensities R, which is measured as emittedphotons/unit time/volume, generating the image includes generating areconstructed three-dimensional emission-intensity image of the ROI, andat least 50% of voxels of the image have inaccuracies of less than 30%of range R. For some applications, the resolution is at least 5×5×5 mm,performing the SPECT imaging procedure includes generating thereconstructed three-dimensional emission-intensity image, and the atleast 50% of the voxels of the image have inaccuracies of less than 15%of range R.

In an embodiment, the radioactivity is less than or equal to 4.5 mCi,and administering includes administering the ^(99m)Tc-containing specieshaving the radioactivity less than or equal to 4.5 mCi. In anembodiment, the radioactivity is less than or equal to 4 mCi, andadministering includes administering the ^(99m)Tc-containing specieshaving the radioactivity less than or equal to 4 mCi. In an embodiment,the radioactivity is less than or equal to 3 mCi, and administeringincludes administering the ^(99m)Tc-containing species having theradioactivity less than or equal to 3 mCi. In an embodiment, theradioactivity is less than or equal to 3 mCi, and administering includesadministering the ^(99m)Tc-containing species having the radioactivityless than or equal to 2 mCi. In an embodiment, the radioactivity is lessthan or equal to 3 mCi, and administering includes administering the^(99m)Tc-containing species having the radioactivity less than or equalto 1 mCi.

In an embodiment, the radioactivity is at least 2 mCi, and administeringincludes administering the ^(99m)Tc-containing species having theradioactivity that is at least 2 mCi.

In an embodiment, administering includes administering the^(99m)Tc-containing species while the subject is at rest, and performingthe SPECT imaging procedure includes performing a SPECT rest imagingprocedure, and including, before or after the administering while thesubject is at rest:

subjecting the subject to stress;

during the stress, administering to the subject a ^(99m)Tc-containingspecies having the formula ^(99m)TcX(Y)₃Z; and

performing a SPECT stress imaging procedure on the subject.

In an embodiment, administering during the stress includes administeringthe ^(99m)Tc-containing species having a radioactivity of less than 18mCi at a time of the administering.

In an embodiment, administering during the stress includes beginning theadministering during the stress within 5 hours of completing the SPECTrest imaging procedure, such as within 1 hour, within 30 minutes, orwithin 10 minutes of completing the SPECT rest imaging procedure.

For some applications, subjecting the subject to stress includessubjecting the subject to pharmacological stress. Alternatively oradditionally, subjecting the subject to stress includes subjecting thesubject to exercise stress.

In an embodiment, performing the SPECT stress imaging procedure includesacquiring at least one in 5000 photons emitted from the ROI during theSPECT stress imaging procedure.

In an embodiment, performing the SPECT stress imaging procedure includesperforming the SPECT stress imaging procedure with an image acquisitionperiod having a duration of no more than 25 minutes, such as no morethan 5 minutes.

There is further provided, in accordance with an embodiment of thepresent invention, apparatus for performing cardiac imaging, includingan imaging system, which includes:

SPECT imaging functionality; and

a control unit configured to drive the imaging functionality to performa SPECT imaging procedure on a cardiac region of interest (ROI) of anadult human subject after administration to the subject of a^(99m)Tc-containing species having a radioactivity of less than 5 mCi ata time of administration, wherein said ^(99m)Tc-containing species hasthe formula ^(99m)TcX(Y)₃Z, wherein:

X is an anion;

each Y, which is independently chosen, is a vicinal dioxime having theformula HON═C(R₁)C(R₂)═NOH or a pharmaceutically acceptable saltthereof, wherein R₁ and R₂ are each independently hydrogen, halogen,alkyl, aryl, amino or a 5 or 6-membered nitrogen or oxygen containingheterocycle, or together R₁ and R₂ are —(CR₈CR₉)_(n)— wherein n is 3, 4,5 or 6 and R₈ and R₉ are each independently hydrogen or alkyl; and

Z is a boron derivative of the formula B—R₃

wherein R₃ is hydroxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy,carboxyalkyl, carboxyalkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl,alkoxyalkenyl, haloalkyl, haloalkenyl, aryl, arylalkyl or (R₄R₅N)-alkyland R₄ and R₅ are each independently hydrogen, alkyl, or arylalkyl, orR₄ and R₅ when taken together with the nitrogen atom to which they areattached form a 5 or 6-membered nitrogen containing heterocycle.

In an embodiment, the control unit is configured to drive the imagingfunctionality to perform a dynamic SPECT imaging procedure.

In an embodiment, the apparatus includes an automated administrationsystem, configured to receive imaging protocol information for use withthe ^(99m)Tc-containing species, and to perform at least one automatedadministration of the ^(99m)Tc-containing species into the subject atleast in part responsively to the protocol information.

In an embodiment, the apparatus includes a container containing the^(99m)Tc-containing species having the radioactivity of less than 5 mCiat the time of administration.

In an embodiment, the apparatus includes a portablecomputer-communicatable data carrier associated with the container, thedata carrier containing imaging protocol information for use with the^(99m)Tc-containing species. For some applications, the apparatusincludes an automated administration system, configured to receiveimaging protocol information for use with the ^(99m)Tc-containingspecies from the data carrier, and to perform at least one automatedadministration of the ^(99m)Tc-containing species into the subject atleast in part responsively to the protocol information.

There is still further provided, in accordance with an embodiment of thepresent invention, apparatus for cardiac imaging, including a portablecomputer-communicatable data carrier, which is configured to containimaging protocol information for performing SPECT imaging on an adulthuman subject, the protocol information including an indication ofadministration of a ^(99m)Tc-containing species of the formula^(99m)TcX(Y)₃Z, wherein:

X is an anion;

each Y, which is independently chosen, is a vicinal dioxime having theformula HON═C(R₁)C(R₂)═NOH or a pharmaceutically acceptable saltthereof, wherein R₁ and R₂ are each independently hydrogen, halogen,alkyl, aryl, amino or a 5 or 6-membered nitrogen or oxygen containingheterocycle, or together R₁ and R₂ are —(CR₈CR₉)_(n)— wherein n is 3, 4,5 or 6 and R₈ and R₉ are each independently hydrogen or alkyl; and

Z is a boron derivative of the formula B—R₃

wherein R₃ is hydroxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy,carboxyalkyl, carboxyalkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl,alkoxyalkenyl, haloalkyl, haloalkenyl, aryl, arylalkyl or (R₄R₅N)-alkyland R₄ and R₅ are each independently hydrogen, alkyl, or arylalkyl, orR₄ and R₅ when taken together with the nitrogen atom to which they areattached form a 5 or 6-membered nitrogen containing heterocycle.

In an embodiment, the protocol information includes an indication of aradioactivity of the ^(99m)Tc-containing species of less than 5 mCi at atime of the administration.

In an embodiment, the protocol information includes an indication ofperformance of a SPECT imaging procedure on the subject, which procedureincludes an image acquisition period having a duration not exceeding 5minutes.

In an embodiment, the protocol information includes an indication ofperformance of a SPECT imaging procedure on the subject, which procedureincludes: (a) a duration of an image acquisition period, and (b) aradioactivity of the ^(99m)Tc-containing species, wherein a product (a)and (b) is less than 50 mCi*minutes.

In an embodiment, the protocol information includes an indication ofperformance of a SPECT imaging procedure on the subject, which procedureincludes: (a) a duration of an image acquisition period, and (b) aradioactivity of the ^(99m)Tc-containing species, wherein a product (a)and (b) is less than 30 mCi*minutes.

In an embodiment, the protocol information includes an indication ofperformance of a SPECT imaging procedure on the subject, which procedureincludes: (a) a duration of an image acquisition period, and (b) aradioactivity of the ^(99m)Tc-containing species, wherein a product (a)and (b) is less than 10 mCi*minutes.

In an embodiment, the apparatus includes a container containing the^(99m)Tc-containing species, and the data carrier is associated with thecontainer.

There is additionally provided, in accordance with an embodiment of thepresent invention apparatus including a container containing a dose of a^(99m)Tc-containing species calculated to have a radioactivity of lessthan 5 mCi at an expected time of administration to an adult humansubject, the ^(99m)Tc-containing species having the formula^(99m)TcX(Y)₃Z, wherein:

X is an anion;

each Y, which is independently chosen, is a vicinal dioxime having theformula HON═C(R₁)C(R₂)═NOH or a pharmaceutically acceptable saltthereof, wherein R₁ and R₂ are each independently hydrogen, halogen,alkyl, aryl, amino or a 5 or 6-membered nitrogen or oxygen containingheterocycle, or together R₁ and R₂ are —(CR₈CR₉)_(n)— wherein n is 3, 4,5 or 6 and R₈ and R₉ are each independently hydrogen or alkyl; and

Z is a boron derivative of the formula B—R₃

wherein R₃ is hydroxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy,carboxyalkyl, carboxyalkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl,alkoxyalkenyl, haloalkyl, haloalkenyl, aryl, arylalkyl or (R₄R₅N)-alkyland R₄ and R₅ are each independently hydrogen, alkyl, or arylalkyl, orR₄ and R₅ when taken together with the nitrogen atom to which they areattached form a 5 or 6-membered nitrogen containing heterocycle.

For some applications, the apparatus includes a portablecomputer-communicatable data carrier associated with the container,which data carrier is configured to contain information indicating thatthe container contains the 99m-Tc-containing species having theradioactivity of less than 5 mCi at said expected time ofadministration. For some applications, the data carrier includes anidentifier of the subject.

For some applications, the container further contains a pharmacologicalstress agent. For some applications, the container further contains avasodilator.

For some applications, the container further contains I-123 BMIPP.

For some applications, the container further contains ^(99m)Tc ECDG.

For some applications, the container further contains^(99m)Tc-sestamibi. For some applications, container further contains^(99m)Tc-tetrofosmin.

For some applications, the dose of the ^(99m)Tc-containing speciesincludes a first dose the ^(99m)Tc-containing species, and the containerfurther contains a second dose of a ^(99m)Tc-containing species havingthe formula ^(99m)TcX(Y)₃Z.

There is still additionally provided, in accordance with an embodimentof the present invention pharmaceutical or diagnostic compositionincluding a ^(99m)Tc-containing species having the formula^(99m)TcX(Y)₃Z, wherein:

X is an anion;

each Y, which is independently chosen, is a vicinal dioxime having theformula HON═C(R₁)C(R₂)═NOH or a pharmaceutically acceptable saltthereof, wherein R₁ and R₂ are each independently hydrogen, halogen,alkyl, aryl, amino or a 5 or 6-membered nitrogen or oxygen containingheterocycle, or together R₁ and R₂ are —(CR₈CR₉)_(n)— wherein n is 3, 4,5 or 6 and R₈ and R₉ are each independently hydrogen or alkyl; and

Z is a boron derivative of the formula B—R₃

wherein R₃ is hydroxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy,carboxyalkyl, carboxyalkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl,alkoxyalkenyl, haloalkyl, haloalkenyl, aryl, arylalkyl or (R₄R₅N)-alkyland R₄ and R₅ are each independently hydrogen, alkyl, or arylalkyl, orR₄ and R₅ when taken together with the nitrogen atom to which they areattached form a 5 or 6-membered nitrogen containing heterocycle,

wherein the ^(99m)Tc radioactivity of the ^(99m)TcX(Y)₃Z in the portionof the composition to be administered to a patient is less than 5 mCi.

For some applications, said composition is in unit dosage form and thedosage unit contains less than 5 mCi ^(99m)Tc radioactivity at a time ofadministration to a human subject.

For some applications, the composition further includes at least oneadditional ^(99m)Tc-containing species different from the^(99m)Tc-containing species having the formula ^(99m)TcX(Y)₃Z, such as^(99m)Tc-sestamibi or ^(99m)Tc-tetrofosmin.

There is also provided, in accordance with an embodiment of the presentinvention, a method for preparing a diagnostic or pharmaceuticalcomposition including a ^(99m)Tc-containing species having aradioactivity of less than 5 mCi at a time of administration, whereinsaid ^(99m)Tc-containing species has the formula ^(99m)TcX(Y)₃Z,wherein:

X is an anion;

each Y, which is independently chosen, is a vicinal dioxime having theformula HON═C(R₁)C(R₂)═NOH or a pharmaceutically acceptable saltthereof, wherein R₁ and R₂ are each independently hydrogen, halogen,alkyl, aryl, amino or a 5 or 6-membered nitrogen or oxygen containingheterocycle, or together R₁ and R₂ are —(CR₈CR₉)_(n)— wherein n is 3, 4,5 or 6 and R₈ and R₉ are each independently hydrogen or alkyl; and

Z is a boron derivative of the formula B—R₃

wherein R₃ is hydroxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy,carboxyalkyl, carboxyalkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl,alkoxyalkenyl, haloalkyl, haloalkenyl, aryl, arylalkyl or (R₄R₅N)-alkyland R₄ and R₅ are each independently hydrogen, alkyl, or arylalkyl, orR₄ and R₅ when taken together with the nitrogen atom to which they areattached form a 5 or 6-membered nitrogen containing heterocycle, themethod including mixing:

(i) a source of anion;

(ii) a boronic acid derivative, or compounds which can react in situ toform a boronic acid derivative, having the formula R₃B(OR₇)(OR₇) or apharmaceutically acceptable salt thereof, wherein R₃ is hydroxy, alkyl,alkenyl, cycloalkyl, cycloalkenyl, alkoxy, carboxyalkyl, carboxyalkenyl,hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, alkoxy-alkenyl, haloalkyl,haloalkenyl, aryl, arylalkyl, or R₄R₅N-alkyl and R₄ and R₅ are eachindependently hydrogen, alkyl, or arylalkyl, or R₄ and R₅ when takentogether with nitrogen atom to which they are attached form a 5 or6-membered nitrogen containing heterocycle, and each R₇ is independentlyselected from hydrogen, alkyl and aryl;

(iii) at least one dioxime having the formula HON═C(R₁)C(R₂)═NOH or apharmaceutically acceptable salt thereof, wherein R₁ and R₂ are eachindependently hydrogen, halogen, alkyl, aryl, amino or a 5 or 6-memberednitrogen or oxygen containing heterocycle, or together R₁ and R₂ are—(CR₈R₉)_(n)— wherein n is 3, 4, 5 or 6 and R₈ and R₉ are eachindependently hydrogen or alkyl;

(iv) a reducing agent; and

(v) a source of ^(99m)Tc having an amount of dispensed radiationcalculated such that an amount of radiation in a portion of thecomposition to be administered to a human subject will be less than 5mCi at an expected time of administration of the portion;

whereby to obtain a composition including ^(99m)Tc and which has lessthan 5 mCi ^(99m)Tc radioactivity at said time of administration.

In an embodiment, mixing includes receiving an indication of theexpected time of administration, and calculating the dispensed radiationresponsively to the indication

For some applications, the method further includes heating the mixedingredients for a time and at a temperature sufficient to form said^(99m)Tc-containing species, such as from about 100° C. to about 140° C.

For some applications, said mixing further includes mixing one or morecomplexing agents.

For some applications, said complexing agent is selected from the groupconsisting of diethylenetriamine-pentaacetic acid, ethyleneglycol-bis(β-aminoethyl ether)-N,N′-tetraacetic acid, ethylenediaminetetraacetic acid, citric acid, tartaric acid and malonic acid.

For some applications, said mixing further includes mixing at least onecatalyst.

For some applications, said at least one catalyst includes anα-hydroxycarboxylic acid. For some applications, saidα-hydroxycarboxylic acid is selected from the group consisting of citricacid, tartaric acid, and malonic acid.

There is further provided, in accordance with an embodiment of thepresent invention, an automated radiopharmaceutical dispensing systemfor use with a container, the system including:

a robot, configured to manipulate the container; and

a control unit, configured to drive the robot to automatically dispense,to the container, a dose of a ^(99m)Tc-containing species having adispensed radioactivity calculated to result in a radioactivity of lessthan 5 mCi at an expected time of administration of the dose, whereinsaid ^(99m)Tc-containing species has the formula ^(99m)TcX(Y)₃Z,wherein:

X is an anion;

each Y, which is independently chosen, is a vicinal dioxime having theformula HON═C(R₁)C(R₂)═NOH or a pharmaceutically acceptable saltthereof, wherein R₁ and R₂ are each independently hydrogen, halogen,alkyl, aryl, amino or a 5 or 6-membered nitrogen or oxygen containingheterocycle, or together R₁ and R₂ are —(CR₈CR₉)_(n)— wherein n is 3, 4,5 or 6 and R₈ and R₉ are each independently hydrogen or alkyl; and

Z is a boron derivative of the formula B—R₃

wherein R₃ is hydroxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy,carboxyalkyl, carboxyalkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl,alkoxyalkenyl, haloalkyl, haloalkenyl, aryl, arylalkyl or (R₄R₅N)-alkyland R₄ and R₅ are each independently hydrogen, alkyl, or arylalkyl, orR₄ and R₅ when taken together with the nitrogen atom to which they areattached form a 5 or 6-membered nitrogen containing heterocycle.

In an embodiment, the control unit is configured to receive anindication of the expected time of administration, and to calculate thedispensed radioactivity responsively to the indication.

There is still further provided, in accordance with an embodiment of thepresent invention, a method for cardiac imaging, including:

administering to an adult human subject a ^(99m)Tc-containing specieshaving a radioactivity of less than 30 mCi at a time of theadministering; and

performing a SPECT imaging procedure on a cardiac region of interest(ROD of the subject with a image acquisition period having a durationnot exceeding 5 minutes,

wherein said ^(99m)Tc-containing species has the formula ^(99m)TcX(Y)₃Z,wherein:

X is an anion;

each Y, which is independently chosen, is a vicinal dioxime having theformula HON═C(R₁)C(R₂)═NOH or a pharmaceutically acceptable saltthereof, wherein R₁ and R₂ are each independently hydrogen, halogen,alkyl, aryl, amino or a 5 or 6-membered nitrogen or oxygen containingheterocycle, or together R₁ and R₂ are —(CR₈CR₉)_(n)— wherein n is 3, 4,5 or 6 and R₈ and R₉ are each independently hydrogen or alkyl;

Z is a boron derivative of the formula B—R₃

wherein R₃ is hydroxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy,carboxyalkyl, carboxyalkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl,alkoxyalkenyl, haloalkyl, haloalkenyl, aryl, arylalkyl or (R₄R₅N)-alkyland R₄ and R₅ are each independently hydrogen, alkyl, or arylalkyl, orR₄ and R₅ when taken together with the nitrogen atom to which they areattached form a 5 or 6-membered nitrogen containing heterocycle.

For some applications, the radioactivity is less than 15 mCi, such asless than 10 mCi, or less than 5 mCi. For some applications, theradioactivity is greater than 1 mCi.

For some applications, the duration of the image acquisition period doesnot exceed 3 minutes, e.g., does not exceed 2.5 minutes, or does notexceed 1 minute.

For some applications, performing the SPECT imaging procedure includes,during the image acquisition period, acquiring a number of photonsemitted from the ^(99m)Tc-containing species which is greater than orequal to at least one of the following numbers:

one in 5000 photons emitted by the ^(99m)Tc-containing species in theROI during the image acquisition period, and

200,000 photons emitted by the ^(99m)Tc-containing species in a portionof the ROI, which portion has a volume of no more than 500 cc.

For some applications, acquiring the number of photons includesacquiring at least one in 5000 photons emitted from the ROI during theimage acquisition period, such as at least one in 2000 or at least onein 1000 photons emitted from the ROI during the image acquisitionperiod.

For some applications, acquiring the number of photons includesacquiring at least 200,000 photons during the image acquisition periodfrom the portion of the ROI having the target volume of no more than 500cc. For some applications, the portion of the ROI has a volume of nomore than 200 cc, and acquiring the number of photons includes acquiringat least 1,000,000 photons during the image acquisition period from theportion of the ROI having the volume of no more than 200 cc.

For some applications, performing the SPECT imaging procedure includesgenerating an image having a resolution of at least 7×7×7 mm. For someapplications, the ^(99m)Tc-containing species as distributed within theROI has a range of emission-intensities R, which is measured as emittedphotons/unit time/volume, performing the SPECT imaging proceduregenerating a reconstructed three-dimensional emission-intensity image ofthe ROI, and at least 50% of voxels of the image have inaccuracies ofless than 30% of range R. For some applications, the resolution is atleast 5×5×5 mm, generating the image includes generating thereconstructed three-dimensional emission-intensity image, and the atleast 50% of the voxels of the image have inaccuracies of less than 15%of range R.

In an embodiment, administering includes administering the^(99m)Tc-containing species while the subject is at rest, and performingthe SPECT imaging procedure includes performing a SPECT rest imagingprocedure, and including, after completion of the SPECT rest imagingprocedure:

subjecting the subject to stress;

during the stress, administering into the subject the^(99m)Tc-containing species having a radioactivity of between 15 and 40mCi at a time of the administering; and

performing a SPECT stress imaging procedure on the subject with a stressimage acquisition period having a duration not exceeding 5 minutes.

For some applications, administering during the stress includesbeginning the administering during the stress within 5 hours ofcompleting the SPECT rest imaging procedure.

In an embodiment, administering includes administering the^(99m)Tc-containing species while the subject is at rest, performing theSPECT imaging procedure includes performing a SPECT rest imagingprocedure, and including, before administering the ^(99m)Tc-containingspecies while the subject is at rest:

subjecting the subject to stress;

during the stress, administering into the subject the^(99m)Tc-containing species having a radioactivity of between 15 and 40mCi at a time of the administering; and

performing a SPECT stress imaging procedure on the subject.

For some applications, performing the SPECT stress imaging procedureincludes performing the SPECT stress imaging procedure with a stressimage acquisition period having a duration not exceeding 5 minutes.

For some applications, the radioactivity of the ^(99m)Tc-containingspecies administered during the stress is between 20 and 40 mCi, such asbetween 25 and 30 mCi.

For some applications, the duration of the stress image acquisitionperiod does not exceed 4 minutes.

For some applications, subjecting the subject to stress includessubjecting the subject to pharmacological stress. For some applications,subjecting the subject to stress includes subjecting the subject toexercise stress. For some applications, subjecting the subject to stressincludes administering a vasodilator prior to subjecting the subject tostress. For example, the vasodilator may include nitroglycerin, andadministering the vasodilator includes administering the nitroglycerin,or the vasodilator may include isosorbide dinitrate, and administeringthe vasodilator includes administering the isosorbide dinitrate.

For some applications, administering the ^(99m)Tc-containing species atrest and during the stress includes administering the^(99m)Tc-containing species using an automated administration systemthat is configured to receive imaging protocol information for use withthe ^(99m)Tc-containing species, and to administer the^(99m)Tc-containing species into the subject at least in partresponsively to the protocol information.

For some applications, administering the ^(99m)Tc-containing species atrest and during the stress and performing the SPECT rest and stressimaging procedures include administering the ^(99m)Tc-containing speciesat rest and during the stress and performing the SPECT rest and stressimaging procedures while the subject remains in place at a camera of animaging system.

For some applications, administering the ^(99m)Tc-containing species atrest and during the stress and performing the SPECT rest and stressimaging procedures include administering the ^(99m)Tc-containing speciesat rest and during the stress and performing the SPECT rest and stressimaging procedures during a time period having a duration of no morethan 30 minutes.

In an embodiment, administering includes administering the^(99m)Tc-containing species while the subject is at rest, performing theSPECT imaging procedure includes performing a SPECT rest imagingprocedure, and the method includes, after completion of the SPECT restimaging procedure:

subjecting the subject to stress;

during the stress, administering to the subject thallium having aradioactivity of between 3 and 5 mCi at a time of the administering; and

performing SPECT stress imaging on the subject.

In an embodiment, administering includes administering the^(99m)Tc-containing species while the subject is at rest, performing theSPECT imaging procedure includes performing a SPECT rest imagingprocedure, and including, before administering the ^(99m)Tc-containingspecies while the subject is at rest:

subjecting the subject to stress;

during the stress, administering to the subject thallium having aradioactivity of between 3 and 5 mCi at a time of the administering; and

performing SPECT stress imaging on the subject.

In an embodiment, administering includes administering the^(99m)Tc-containing species while the subject is at rest, performing theSPECT imaging procedure includes performing a SPECT rest imagingprocedure, and including:

before administering the ^(99m)Tc-containing species while the subjectis at rest:

-   -   subjecting the subject to stress; and    -   during the stress, administering to the subject thallium having        a radioactivity of between 3 and 5 mCi at a time of the        administering; and

after administering the ^(99m)Tc-containing species and the thallium,and before performing the SPECT rest imaging procedure, performing SPECTstress imaging on the subject.

In an embodiment, administering includes administering the^(99m)Tc-containing species while the subject is at rest, performing theSPECT imaging procedure includes performing a SPECT rest imagingprocedure, and including:

before administering the ^(99m)Tc-containing species while the subjectis at rest:

-   -   subjecting the subject to stress; and    -   during the stress, administering to the subject thallium having        a radioactivity of between 3 and 5 mCi at a time of the        administering; and

after administering the ^(99m)Tc-containing species and the thallium,performing SPECT stress imaging on the subject simultaneously withperforming the SPECT rest imaging procedure.

In an embodiment,

administering includes subjecting the subject to stress, andadministering the ^(99m)Tc-containing species during the stress,

performing the SPECT imaging procedure includes performing a SPECTstress imaging procedure of the ^(99m)Tc-containing species, andincluding:

after administering the ^(99m)Tc-containing species, administering tothe subject, while the subject is at rest, thallium having aradioactivity of between 3 and 5 mCi at a time of the administering; and

after performing the SPECT stress imaging procedure, performing a SPECTrest imaging procedure of the thallium.

In an embodiment,

administering includes subjecting the subject to stress, andadministering the ^(99m)Tc-containing species during the stress,

performing the SPECT imaging procedure includes performing a SPECTstress imaging procedure of the ^(99m)Tc-containing species, andincluding:

before administering the ^(99m)Tc-containing species, administering tothe subject, while the subject is at rest, thallium having aradioactivity of between 3 and 5 mCi at a time of the administering; and

after administering the ^(99m)Tc-containing species and the thallium,performing a SPECT rest imaging procedure of the thallium, beforeperforming the SPECT stress imaging procedure of the ^(99m)Tc-containingspecies.

In an embodiment,

administering includes subjecting the subject to stress, andadministering the ^(99m)Tc-containing species during the stress,

performing the SPECT imaging procedure includes performing a SPECTstress imaging procedure of the ^(99m)Tc-containing species, andincluding:

before administering the ^(99m)Tc-containing species, administering tothe subject, while the subject is at rest, thallium having aradioactivity of between 3 and 5 mCi at a time of the administering; and

after administering the ^(99m)Tc-containing species and the thallium,performing a SPECT rest imaging of the thallium simultaneously withperforming the SPECT stress imaging procedure of the ^(99m)Tc-containingspecies.

For some applications, subjecting the subject to stress includessubjecting the subject to pharmacological stress.

For some applications, subjecting the subject to stress includessubjecting the subject to exercise stress.

For some applications, administering the ^(99m)Tc-containing species andadministering the thallium include administering the ^(99m)Tc-containingspecies and the thallium using an automated administration system thatis configured to receive imaging protocol information for use with the^(99m)Tc-containing species and the thallium, and to administer the^(99m)Tc-containing species and the thallium into the subject at leastin part responsively to the protocol information.

For some applications, administering the ^(99m)Tc-containing species,administering the thallium, performing the SPECT rest imaging procedure,and performing the SPECT stress imaging procedure include administeringthe ^(99m)Tc-containing species, administering the thallium, performingthe SPECT rest imaging procedure, and performing the SPECT stressimaging procedure while the subject remains in place at a camera of animaging system.

For some applications, administering the ^(99m)Tc-containing species,administering the thallium, performing the SPECT rest imaging procedure,and performing the SPECT stress imaging procedure include administeringthe ^(99m)Tc-containing species, administering the thallium, performingthe SPECT rest imaging procedure, and performing the SPECT stressimaging procedure during a time period having a duration of no more than30 minutes, such as no more than 20 minutes, or no more than 15 minutes.

For some applications, the method includes processing data acquired fromthe stress imaging to provide a clinically-valuable image.

For some applications, performing the SPECT stress imaging includesperforming the SPECT stress imaging for a duration not exceeding 5minutes.

In an embodiment, the method includes, prior to or during performance ofthe SPECT imaging procedure, administering to the subject I-123 BMIPP ata radioactivity of between 3 and 5 mCi at a time of the administering,and performing the SPECT rest imaging procedure includes simultaneouslyimaging the ^(99m)Tc-containing species and the I-123 BMIPP. For someapplications, imaging the I-123 BMIPP includes acquiring, during therest image acquisition period, a number of photons emitted by the I-123BMIPP which is greater than or equal to at least one of the followingnumbers:

one in 5000 photons emitted by the I-123 BMIPP in the ROI during therest image acquisition period, and

200,000 photons emitted by the I-123 BMIPP in a portion of the ROI,which portion has a volume of no more than 500 cc.

In an embodiment, administering includes administering the^(99m)Tc-containing species while the subject is at rest, performing theSPECT imaging procedure includes performing a SPECT rest imagingprocedure, and the method includes, after completion of the SPECT restimaging procedure:

subjecting the subject to stress;

during the stress, administering to the subject Tc-99m ECDG having aradioactivity of less than 35 mCi at a time of the administering; and

performing a SPECT stress imaging procedure on the subject.

In an embodiment, performing the SPECT imaging procedure includesperforming a first SPECT imaging procedure, and including, aftercompletion of the first SPECT imaging procedure:

administering to the subject at least one additional ^(99m)Tc-containingspecies different from the ^(99m)Tc-containing species having theformula ^(99m)TcX(Y)₃Z; and

performing a second SPECT imaging procedure using the at least oneadditional ^(99m)Tc-containing species.

For some applications, the at least one additional ^(99m)Tc-containingspecies includes ^(99m)Tc-sestamibi. For some applications, the at leastone additional ^(99m)Tc-containing species includes^(99m)Tc-tetrofosmin.

In an embodiment,

administering the ^(99m)Tc-containing species includes administering the^(99m)Tc-containing species while the subject is at rest,

performing the first SPECT imaging procedure includes performing a firstSPECT rest imaging procedure,

administering the at least one additional ^(99m)Tc-containing speciesincludes subject the subject to stress, and administering the at leastone additional ^(99m)Tc-containing species, and

performing the second SPECT imaging procedure includes performing asecond SPECT stress imaging procedure.

In an embodiment,

administering the ^(99m)Tc-containing species includes subjecting thesubject to stress, and administering the ^(99m)Tc-containing speciesduring the stress,

performing the first SPECT imaging procedure includes performing a firstSPECT stress imaging procedure,

administering the at least one additional ^(99m)Tc-containing speciesincludes administering the at least one additional ^(99m)Tc-containingspecies when the subject is at rest, and

performing the second SPECT imaging procedure includes performing asecond SPECT rest imaging procedure.

In an embodiment, performing the SPECT imaging procedure includesperforming a first SPECT imaging procedure, and including:

prior to administering the ^(99m)Tc-containing species:

-   -   administering to the subject at least one additional        ^(99m)Tc-containing species different from the        ^(99m)Tc-containing species having the formula ^(99m)TcX(Y)₃Z;        and    -   performing a first portion of a second SPECT imaging procedure        using the at least one additional ^(99m)Tc-containing species,

administering the ^(99m)Tc-containing species includes administering the^(99m)Tc-containing species after performing the first portion of thesecond SPECT imaging procedure,

performing the first SPECT imaging procedure includes performing thefirst SPECT imaging procedure after administering the^(99m)Tc-containing species, and

including performing a second portion of the second SPECT imagingprocedure after completing performing of the first SPECT imagingprocedure.

In an embodiment, administering the ^(99m)Tc-containing species includesadministering the ^(99m)Tc-containing species while the subject is atrest, performing the SPECT imaging procedure includes performing a SPECTrest imaging procedure, and including:

prior to administering the ^(99m)Tc-containing species:

-   -   subjecting the subject to stress;    -   during the stress, administering to the subject at least one        additional ^(99m)Tc-containing species different from the        ^(99m)Tc-containing species having the formula ^(99m)TcX(Y)₃Z;        and

after performing the SPECT rest imaging procedure, performing a SPECTstress imaging procedure using the at least one additional^(99m)Tc-containing species.

For some applications, the at least one additional ^(99m)Tc-containingspecies includes ^(99m)Tc-sestamibi. For some applications, the at leastone additional ^(99m)Tc-containing species includes^(99m)Tc-tetrofosmin.

There is additionally provided, in accordance with an embodiment of thepresent invention, apparatus for performing cardiac imaging, includingan imaging system, which includes:

SPECT imaging functionality; and

a control unit configured to drive the imaging functionality to performa SPECT imaging procedure on a cardiac region of interest (ROI) of anadult human subject after administration to the subject of a^(99m)Tc-containing species having a radioactivity of less than 30 mCiat a time of the administration, wherein the imaging procedure has aimage acquisition period having a duration not exceeding 5 minutes, and

wherein said ^(99m)Tc-containing species has the formula ^(99m)TcX(Y)₃Z,wherein:

X is an anion;

each Y, which is independently chosen, is a vicinal dioxime having theformula HON═C(R₁)C(R₂)═NOH or a pharmaceutically acceptable saltthereof, wherein R₁ and R₂ are each independently hydrogen, halogen,alkyl, aryl, amino or a 5 or 6-membered nitrogen or oxygen containingheterocycle, or together R₁ and R₂ are —(CR₈CR₉)_(n)— wherein n is 3, 4,5 or 6 and R₈ and R₉ are each independently hydrogen or alkyl; and

Z is a boron derivative of the formula B—R₃

wherein R₃ is hydroxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy,carboxyalkyl, carboxyalkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl,alkoxyalkenyl, haloalkyl, haloalkenyl, aryl, arylalkyl or (R₄R₅N)-alkyland R₄ and R₅ are each independently hydrogen, alkyl, or arylalkyl, orR₄ and R₅ when taken together with the nitrogen atom to which they areattached form a 5 or 6-membered nitrogen containing heterocycle.

For some applications, the radioactivity is less than 15 mCi, such asless than 10 mCi, or less than 5 mCi. For some applications, theradioactivity is greater than 1 mCi.

For some applications, the control unit is configured to, during theimage acquisition period, acquire a number of photons greater than orequal to at least one of the following numbers:

one in 5000 photons emitted from the ROI during the image acquisitionperiod, and

200,000 photons emitted from a portion of the ROI, which portion has avolume of no more than 500 cc.

For some applications, the control unit is configured to drive theimaging functionality to perform a dynamic SPECT imaging procedure.

In an embodiment, the apparatus includes an automated administrationsystem, configured to receive imaging protocol information for use withthe ^(99m)Tc-containing species, and to perform at least one automatedadministration of the ^(99m)Tc-containing species into the subject atleast in part responsively to the protocol information.

In an embodiment, the apparatus includes a container containing the^(99m)Tc-containing species. For some applications, the apparatusincludes a portable computer-communicatable data carrier associated withthe container, the data carrier containing imaging protocol informationfor use with the ^(99m)Tc-containing species. For some applications, theapparatus includes an automated administration system, configured toreceive imaging protocol information for use with the^(99m)Tc-containing species from the data carrier, and to perform atleast one automated administration of the ^(99m)Tc-containing speciesinto the subject at least in part responsively to the protocolinformation.

There is still additionally provided, in accordance with an embodimentof the present invention, apparatus for cardiac imaging, including aportable computer-communicatable data carrier, which is configured tocontain imaging protocol information for performing SPECT imaging on anadult human subject, the protocol information including an indication ofadministration of ^(99m)Tc-containing species having a radioactivity ofless than 30 mCi at a time of the administration, and performance of aSPECT imaging procedure with a image acquisition period having aduration not exceeding 5 minutes,

wherein said ^(99m)Tc-containing species has the formula ^(99m)TcX(Y)₃Z,wherein:

X is an anion;

each Y, which is independently chosen, is a vicinal dioxime having theformula HON═C(R₁)C(R₂)═NOH or a pharmaceutically acceptable saltthereof, wherein R₁ and R₂ are each independently hydrogen, halogen,alkyl, aryl, amino or a 5 or 6-membered nitrogen or oxygen containingheterocycle, or together R₁ and R₂ are —(CR₈CR₉)_(n)— wherein n is 3, 4,5 or 6 and R₈ and R₉ are each independently hydrogen or alkyl; and

Z is a boron derivative of the formula B—R₃

wherein R₃ is hydroxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy,carboxyalkyl, carboxyalkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl,alkoxyalkenyl, haloalkyl, haloalkenyl, aryl, arylalkyl or (R₄R₅N)-alkyland R₄ and R₅ are each independently hydrogen, alkyl, or arylalkyl, orR₄ and R₅ when taken together with the nitrogen atom to which they areattached form a 5 or 6-membered nitrogen containing heterocycle.

For some applications, the radioactivity is less than 15 mCi, such asless than 10 mCi, or less than 5 mCi. For some applications, theradioactivity is greater than 1 mCi.

In an embodiment, the apparatus includes a container containing the^(99m)Tc-containing species, and the data carrier is associated with thecontainer.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, a method for cardiac imaging, including:

subjecting a subject to stress;

during the stress, administering to the subject a ^(99m)Tc-containingspecies having a radioactivity of between 20 and 40 mCi at a time of theadministering; and

performing a SPECT stress imaging procedure on a cardiac region ofinterest (ROI) of the subject, with an image acquisition period having aduration not exceeding 5 minutes; and

during the stress image acquisition period, acquiring a number ofphotons greater than or equal to at least one of the following numbers:

one in 5000 photons emitted from the ROI during the stress imageacquisition period, and

200,000 photons emitted from a portion of the ROI, which portion has avolume of no more than 500 cc,

wherein said ^(99m)Tc-containing species has the formula ^(99m)TcX(Y)₃Z,wherein:

X is an anion;

each Y, which is independently chosen, is a vicinal dioxime having theformula HON═C(R₁)C(R₂)═NOH or a pharmaceutically acceptable saltthereof, wherein R₁ and R₂ are each independently hydrogen, halogen,alkyl, aryl, amino or a 5 or 6-membered nitrogen or oxygen containingheterocycle, or together R₁ and R₂ are —(CR₈CR₉)_(n)— wherein n is 3, 4,5 or 6 and R₈ and R₉ are each independently hydrogen or alkyl; and

Z is a boron derivative of the formula B—R₃

wherein R₃ is hydroxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy;carboxyalkyl, carboxyalkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl,alkoxyalkenyl, haloalkyl, haloalkenyl, aryl, arylalkyl or (R₄R₅N)-alkyland R₄ and R₅ are each independently hydrogen, alkyl, or arylalkyl, orR₄ and R₅ when taken together with the nitrogen atom to which they areattached form a 5 or 6-membered nitrogen containing heterocycle.

For some applications, acquiring the number of photons during the stressimage acquisition periods includes acquiring at least one in 2000photons emitted from the ROI during the stress image acquisition period,such as at least one in 1000 photons emitted from the ROI during thestress image acquisition period.

For some applications, acquiring the number of photons during the stressimage acquisition periods includes acquiring at least 500,000 photonsemitted from the portion of the ROI, such as least 1,000,000 or at least2,000,000 photons emitted from the portion of the ROI.

For some applications, the duration of the SPECT rest imaging does notexceed 4 minutes, e.g., does not exceed 2 minutes, does not exceed 1minute, or does not exceed 30 seconds.

For some applications, performing the SPECT stress imaging procedureincludes performing three-dimensional analysis in frames, each of whichhas a duration of between 7 and 13 seconds.

For some applications, subjecting the subject to stress includessubjecting the subject to pharmacological stress. Alternatively oradditionally, subjecting the subject to stress includes subjecting thesubject to exercise stress.

In an embodiment, the method includes, prior to subjecting the subjectto the stress:

administering, while the subject is at rest, thallium to the subjecthaving a radioactivity of between 2 and 5 mCi at a time of theadministering; and

performing SPECT rest imaging on the subject for a duration notexceeding 3 minutes.

For some applications, the method includes processing data acquired fromthe rest imaging to provide a clinically-valuable image.

In an embodiment, the method includes, after completion of the stressimage acquisition period:

administering to the subject I-123 BMIPP at a radioactivity of between 3and 5 mCi at a time of the administering;

performing SPECT BMIPP imaging on the subject; and

acquiring at least one in 5000 photons emitted from the ROI during theBMIPP imaging.

There is also provided, in accordance with an embodiment of the presentinvention, a method for cardiac imaging, including performing a SPECTimaging procedure having a total imaging procedure duration of no morethan 20 minutes, by:

performing first and second administrations of first and secondradiopharmaceutical agents to a subject, respectively, and at least oneof the first and second radiopharmaceutical agents includes a^(99m)Tc-containing species,

performing, during a rest image acquisition period, rest SPECT imagingon a cardiac region of interest (ROI) of the subject,

performing, during a stress image acquisition period, stress SPECTimaging on the ROI, and

during each of the rest and stress image acquisition periods, acquiringa number of photons greater than or equal to at least one of thefollowing numbers:

one in 5000 photons emitted from the ROI during the image acquisitionperiod, and

200,000 photons emitted from a portion of the ROI, which portion has avolume of no more than 500 cc,

wherein said ^(99m)Tc-containing species has the formula ^(99m)TcX(Y)₃Z,wherein:

X is an anion;

each Y, which is independently chosen, is a vicinal dioxime having theformula HON═C(R₁)C(R₂)═NOH or a pharmaceutically acceptable saltthereof, wherein R₁ and R₂ are each independently hydrogen, halogen,alkyl, aryl, amino or a 5 or 6-membered nitrogen or oxygen containingheterocycle, or together R₁ and R₂ are —(CR₈CR₉)_(n)— wherein n is 3, 4,5 or 6 and R₈ and R₉ are each independently hydrogen or alkyl; and

Z is a boron derivative of the formula B—R₃

wherein R₃ is hydroxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy,carboxyalkyl, carboxyalkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl,alkoxyalkenyl, haloalkyl, haloalkenyl, aryl, arylalkyl or (R₄R₅N)-alkyland R₄ and R₅ are each independently hydrogen, alkyl, or arylalkyl, orR₄ and R₅ when taken together with the nitrogen atom to which they areattached form a 5 or 6-membered nitrogen containing heterocycle.

In an embodiment, both the first and second radiopharmaceutical agentsinclude the ^(99m)Tc-containing species.

In an embodiment, at least one of the first and secondradiopharmaceutical agents includes thallium.

For some applications, the total imaging procedure duration is no morethan 15 minutes.

There is also provided, in accordance with an embodiment of the presentinvention, apparatus for performing cardiac imaging, including animaging system, which includes:

SPECT imaging functionality;

an automated administration system; and

a control unit, configured to perform a SPECT imaging procedure having atotal imaging procedure duration of no more than 20 minutes, by:

driving the automated administration system to perform first and secondadministrations of first and second radiopharmaceutical agents to asubject, respectively, wherein at least one of the first and secondradiopharmaceutical agents includes a ^(99m)Tc-containing species, and

driving the imaging functionality to:

perform, during a rest image acquisition period, rest SPECT imaging on acardiac region of interest (ROI) of the subject,

perform, during a stress image acquisition period, stress SPECT imagingon the ROI, and

during each of the rest and stress image acquisition periods, acquire anumber of photons greater than or equal to at least one of the followingnumbers:

one in 5000 photons emitted from the ROI during the image acquisitionperiod, and

200,000 photons emitted from a portion of the ROI, which portion has avolume of no more than 500 cc, wherein said ^(99m)Tc-containing specieshas the formula ^(99m)TcX(Y)₃Z, wherein:

X is an anion;

each Y, which is independently chosen, is a vicinal dioxime having theformula HON═C(R₁)C(R₂)═NOH or a pharmaceutically acceptable saltthereof, wherein R₁ and R₂ are each independently hydrogen, halogen,alkyl, aryl, amino or a 5 or 6-membered nitrogen or oxygen containingheterocycle, or together R₁ and R₂ are —(CR₈CR₉)_(n)— wherein n is 3, 4,5 or 6 and R₈ and R₉ are each independently hydrogen or alkyl; and

Z is a boron derivative of the formula B—R₃

wherein R₃ is hydroxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy,carboxyalkyl, carboxyalkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl,alkoxyalkenyl, haloalkyl, haloalkenyl, aryl, arylalkyl or (R₄R₅N)-alkyland R₄ and R₅ are each independently hydrogen, alkyl, or arylalkyl, orR₄ and R₅ when taken together with the nitrogen atom to which they areattached form a 5 or 6-membered nitrogen containing heterocycle.

There is further provided, in accordance with an embodiment of thepresent invention, a method for cardiac imaging, including:

administering a ^(99m)Tc-containing species to an adult human subject;

performing a SPECT imaging procedure on a cardiac region of interest(ROI) of the subject; and

during the SPECT imaging procedure, acquiring at least one in 5000photons emitted from the ^(99m)Tc-containing species in the ROI duringthe SPECT imaging acquisition procedure,

wherein said ^(99m)Tc-containing species has the formula ^(99m)TcX(Y)₃Z,wherein:

X is an anion;

each Y, which is independently chosen, is a vicinal dioxime having theformula HON═C(R₁)C(R₂)═NOH or a pharmaceutically acceptable saltthereof, wherein R₁ and R₂ are each independently hydrogen, halogen,alkyl, aryl, amino or a 5 or 6-membered nitrogen or oxygen containingheterocycle, or together R₁ and R₂ are —(CR₈CR₉)_(n)— wherein n is 3, 4,5 or 6 and R₈ and R₉ are each independently hydrogen or alkyl; and

Z is a boron derivative of the formula B—R₃

wherein R₃ is hydroxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy,carboxyalkyl, carboxyalkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl,alkoxyalkenyl, haloalkyl, haloalkenyl, aryl, arylalkyl or (R₄R₅N)-alkyland R₄ and R₅ are each independently hydrogen, alkyl, or arylalkyl, orR₄ and R₅ when taken together with the nitrogen atom to which they areattached form a 5 or 6-membered nitrogen containing heterocycle.

In an embodiment, administering the ^(99m)Tc-containing species includesadministering the ^(99m)Tc-containing species with a radioactivity at atime of the administering, and a product of (a) a duration of the SPECTimaging procedure and (b) the radioactivity is less than 50 mCi*minutes,such as less than 30 mCi*minutes, or less than 10 mCi*minutes.

There is still further provided, in accordance with an embodiment of thepresent invention, apparatus for performing cardiac imaging on a humansubject to whom ^(99m)Tc-containing species has been administered, theapparatus including an imaging system, which includes:

SPECT imaging functionality; and

a control unit configured to drive the imaging functionality to:

perform a SPECT imaging procedure on a cardiac region of interest (ROI)of the subject, and

during the SPECT imaging procedure, acquire at least one in 5000 photonsemitted from the ^(99m)Tc-containing species in the ROI during the SPECTimaging procedure,

wherein said ^(99m)Tc-containing species has the formula ^(99m)TcX(Y)₃Z,wherein:

X is an anion;

each Y, which is independently chosen, is a vicinal dioxime having theformula HON═C(R₁)C(R₂)═NOH or a pharmaceutically acceptable saltthereof, wherein R₁ and R₂ are each independently hydrogen, halogen,alkyl, aryl, amino or a 5 or 6-membered nitrogen or oxygen containingheterocycle, or together R₁ and R₂ are —(CR₈CR₉)_(n)— wherein n is 3, 4,5 or 6 and R₈ and R₉ are each independently hydrogen or alkyl; and

Z is a boron derivative of the formula B—R₃

wherein R₃ is hydroxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy,carboxyalkyl, carboxyalkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl,alkoxyalkenyl, haloalkyl, haloalkenyl, aryl, arylalkyl or (R₄R₅N)-alkyland R₄ and R₅ are each independently hydrogen, alkyl, or arylalkyl, orR₄ and R₅ when taken together with the nitrogen atom to which they areattached form a 5 or 6-membered nitrogen containing heterocycle.

There is also provided, in accordance with an embodiment of the presentinvention a method for cardiac imaging, including:

while a subject is at rest, performing a rest administration to thesubject of a ^(99m)Tc-containing species;

after completion of the rest administration, performing a flushadministration to the subject;

beginning less than 10 seconds of the completion of the flushadministration, performing a low-resolution SPECT rest imaging procedureon a cardiac region of interest (ROD of the subject, with alow-resolution rest image acquisition period having a duration between20 and 40 seconds, wherein the low-resolution SPECT rest imagingprocedure includes a plurality of low-resolution rest frames having anaverage low-resolution rest frame duration;

beginning less than 10 seconds after completion of the low-resolutionSPECT rest imaging procedure, performing a high-resolution SPECT restimaging procedure on the ROI, with a high-resolution rest imageacquisition period having a duration of between 4 and 6 minutes, thehigh-resolution SPECT rest imaging procedure includes a plurality ofhigh-resolution rest frames having an average high-resolution frameduration that is at least 2 times the average low-resolution rest frameduration;

after completion of the high-resolution SPECT rest imaging procedure,subjecting the subject to stress;

after subjecting the subject to the stress, performing a stressadministration to the subject of a ^(99m)Tc-containing species;

after the stress administration, performing a low-resolution SPECTstress imaging procedure on a cardiac region of interest (ROD of thesubject, with a low-resolution stress image acquisition period having aduration between 20 and 40 seconds, wherein the low-resolution SPECTstress imaging procedure includes a plurality of low-resolution stressframes having an average low-resolution stress frame duration; and

after completion of the low-resolution SPECT stress imaging procedure,performing a high-resolution SPECT stress imaging procedure on the ROI,with a high-resolution stress image acquisition period having a durationof between 4 and 6 minutes, wherein the high-resolution SPECT stressimaging procedure includes a plurality of high-resolution stress frameshaving an average high-resolution stress frame duration that is at least2 times the average low-resolution stress frame duration,

wherein said ^(99m)Tc-containing species has the formula ^(99m)TcX(Y)₃Z,wherein:

X is an anion;

each Y, which is independently chosen, is a vicinal dioxime having theformula HON═C(R₁)C(R₂)═NOH or a pharmaceutically acceptable saltthereof, wherein R₁ and R₂ are each independently hydrogen, halogen,alkyl, aryl, amino or a 5 or 6-membered nitrogen or oxygen containingheterocycle, or together R₁ and R₂ are —(CR₈CR₉)_(n)— wherein n is 3, 4,5 or 6 and R₈ and R₉ are each independently hydrogen or alkyl; and

Z is a boron derivative of the formula B—R₃

wherein R₃ is hydroxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy,carboxyalkyl, carboxyalkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl,alkoxyalkenyl, haloalkyl, haloalkenyl, aryl, arylalkyl or (R₄R₅N)-alkyland R₄ and R₅ are each independently hydrogen, alkyl, or arylalkyl, orR₄ and R₅ when taken together with the nitrogen atom to which they areattached form a 5 or 6-membered nitrogen containing heterocycle.

In an embodiment, the ^(99m)Tc-containing species administered while thesubject is at rest has a radioactivity of between 6 and 15 mCi at a timeof the rest administration. In an embodiment, the average low-resolutionrest frame duration is between 3 and 7 seconds.

For some applications, performing the low-resolution SPECT rest imagingprocedure includes acquiring on average during each of thelow-resolution rest frames at least 200,000 photons emitted from theROI. For some applications, performing the low-resolution SPECT restimaging procedure includes estimating an input function.

For some applications, the average high-resolution rest frame durationis at least 3 times the average low-resolution rest frame duration. Forsome applications, the average high-resolution rest frame duration isbetween 15 and 25 seconds.

For some applications, performing the high-resolution SPECT rest imagingprocedure includes acquiring on average during each of thehigh-resolution rest frames at least 200,000 photons emitted from theROI.

For some applications, the ^(99m)Tc-containing species administeredafter subjecting the subject to stress has a radioactivity of between 20and 40 mCi at a time of the stress administration.

For some applications, the average low-resolution stress frame durationis between 3 and 7 seconds.

For some applications, performing the low-resolution SPECT stressimaging procedure includes acquiring on average during each of thelow-resolution stress frames at least 600,000 photons emitted from theROI.

For some applications, performing the low-resolution SPECT stressimaging procedure includes estimating counts in a cardiac blood pool.

For some applications, the average high-resolution stress frame durationis at least 3 times the average low-resolution stress frame duration.For some applications, the average high-resolution stress frame durationis between 15 and 25 seconds.

For some applications, performing the high-resolution SPECT stressimaging procedure includes acquiring on average during each of thehigh-resolution stress frames at least 600,000 photons emitted from theROI.

For some applications, subjecting the subject to stress includessubjecting the subject to pharmacological stress. Alternatively oradditionally, subjecting the subject to stress includes subjecting thesubject to exercise stress.

There is further provided, in accordance with an embodiment of thepresent invention, a method for cardiac imaging, including:

administering to an adult human subject a first ^(99m)Tc-containingspecies;

performing a SPECT rest imaging procedure on a cardiac region ofinterest (ROI) of the subject;

during the rest imaging procedure, acquiring a number of photons emittedfrom the first ^(99m)Tc-containing species which is greater than orequal to at least one of the following numbers:

one in 5000 photons emitted by the first ^(99m)Tc-containing species inthe ROI during the rest imaging procedure, and

200,000 photons emitted by the first ^(99m)Tc-containing species in aportion of the ROI, which portion has a volume of no more than 500 cc;

subjecting the subject to stress;

during the stress, and within 5 hours of completing the rest imagingprocedure, administering to the subject a second ^(99m)Tc-containingspecies;

performing a SPECT stress imaging procedure on the ROI; and

during the stress imaging procedure, acquiring a number of photonsemitted from the second ^(99m)Tc-containing species which is greaterthan or equal to at least one of the following numbers:

one in 5000 photons emitted by the second ^(99m)Tc-containing species inthe ROI during the rest imaging procedure, and

200,000 photons emitted by the second ^(99m)Tc-containing species in aportion of the ROI, which portion has a volume of no more than 500 cc,

wherein the second ^(99m)Tc-containing species has the formula^(99m)TcX(Y)₃Z, wherein:

X is an anion;

each Y, which is independently chosen, is a vicinal dioxime having theformula HON═C(R₁)C(R₂)═NOH or a pharmaceutically acceptable saltthereof, wherein R₁ and R₂ are each independently hydrogen, halogen,alkyl, aryl, amino or a 5 or 6-membered nitrogen or oxygen containingheterocycle, or together R₁ and R₂ are —(CR₈CR₉)_(n)— wherein n is 3, 4,5 or 6 and R₈ and R₉ are each independently hydrogen or alkyl; and

Z is a boron derivative of the formula B—R₃

wherein R₃ is hydroxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy,carboxyalkyl, carboxyalkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl,alkoxyalkenyl, haloalkyl, haloalkenyl, aryl, arylalkyl or (R₄R₅N)-alkyland R₄ and R₅ are each independently hydrogen, alkyl, or arylalkyl, orR₄ and R₅ when taken together with the nitrogen atom to which they areattached form a 5 or 6-membered nitrogen containing heterocycle.

For some applications, performing the rest imaging procedure includesperforming the rest imaging procedure having a rest image acquisitionperiod having a duration not exceeding 5 minutes.

In an embodiment, the first ^(99m)Tc-containing species has the formula^(99m)TcX(Y)₃Z, wherein:

X is an anion;

each Y, which is independently chosen, is a vicinal dioxime having theformula HON═C(R₁)C(R₂)═NOH or a pharmaceutically acceptable saltthereof, wherein R₁ and R₂ are each independently hydrogen, halogen,alkyl, aryl, amino or a 5 or 6-membered nitrogen or oxygen containingheterocycle, or together R₁ and R₂ are —(CR₈CR₉)_(n)— wherein n is 3, 4,5 or 6 and R₈ and R₉ are each independently hydrogen or alkyl; and

Z is a boron derivative of the formula B—R₃

wherein R₃ is hydroxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy,carboxyalkyl, carboxyalkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl,alkoxyalkenyl, haloalkyl, haloalkenyl, aryl, arylalkyl or (R₄R₅N)-alkyland R₄ and R₅ are each independently hydrogen, alkyl, or arylalkyl, orR₄ and R₅ when taken together with the nitrogen atom to which they areattached form a 5 or 6-membered nitrogen containing heterocycle.

For some applications, the first ^(99m)Tc-containing species includes^(99m)Tc-sestamibi, ^(99m)Tc-tetrofosmin, ^(99m)Tc-Hynic Annexin, or^(99m)Tc-TcN-NOET.

For some applications, administering the second ^(99m)Tc-containingspecies includes administering the second ^(99m)Tc-containing specieswithin 2 hours of completing the rest imaging procedure, such as within1 hour of completing the rest imaging procedure, within 30 minutes ofcompleting the rest imaging procedure, or within 10 minutes ofcompleting the rest imaging procedure.

There is still further provided, in accordance with an embodiment of thepresent invention, a method for imaging, including:

setting one or more parameters of an imaging procedure for a subjectwhile the subject is positioned at a camera of an imaging system;

performing a first scan of the subject using the one or more parameters;and

performing a second scan of the subject using the one or moreparameters.

There is additionally provided, in accordance with an embodiment of thepresent invention, apparatus including:

a container containing one or more radiopharmaceuticals for use with oneof the protocols described herein; and

an information carrier containing protocol information relating to theone of the protocols.

There is still additionally provided, in accordance with an embodimentof the present invention, a camera configured to perform one of theprotocols described herein.

The present invention will be more fully understood from the followingdetailed description of embodiments thereof, taken together with thedrawings, in which:

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a graph showing the average teboroxime uptake as a function oftime post-injection for the heart, liver, and background, as known inthe prior art;

FIG. 2 is a schematic illustration of an imaging system, in accordancewith an embodiment of the present invention;

FIG. 3 is a schematic illustration of an end-to-end automated system formedical imaging, in accordance with an embodiment of the presentinvention;

FIG. 4 is a schematic illustration of an automated administrationsystem, in accordance with an embodiment of the present invention;

FIG. 5 is a schematic illustration of an automated radiopharmaceuticaldispensing system, in accordance with an embodiment of the presentinvention;

FIGS. 6A-L are timelines illustrating teboroxime imaging protocols, inaccordance with respective embodiments of the present invention;

FIG. 7 is a graph showing hypothesized teboroxime uptake over time inthe liver and the vicinity of the liver in cases in which a tumor hasuptake similar to vascularized tissue, in accordance with an embodimentof the present invention;

FIG. 8 is a graph showing input curves, in accordance with an embodimentof the present invention; and

FIG. 9 shows a series of mid-ventricular slice images produced by thesimulation during the first four minutes after the simulated teboroximeinjection, in accordance with an embodiment of the present invention.

DETAILED DESCRIPTION OF EMBODIMENTS

Overview of Imaging System

FIG. 2 is a schematic illustration of a SPECT imaging system 10, inaccordance with an embodiment of the present invention. Imaging system10 comprises a control unit 20, a camera 22, and an imaging workstation24. Typically, control unit 20 and imaging workstation 24 comprise oneor more standard personal computers or servers with appropriate memory,communication interfaces and software for carrying out the functionsprescribed by relevant embodiments of the present invention. Thissoftware may be downloaded to the control unit and imaging workstationin electronic form over a network, for example, or it may alternativelybe supplied on tangible media, such as CD-ROM.

Control unit 20 typically comprises: (a) image acquisitionfunctionality, which is configured to drive camera 22 to perform imageacquisition of the patient; (b) image reconstruction functionality,which is configured to perform an image reconstruction procedure on theacquired image; (c) image analysis functionality, which is configured toperform an image analysis procedure on the reconstructed image; and (d)diagnosis functionality, which is configured to perform a diagnosticprocedure using the results of the image analysis procedure. It will beappreciated that control unit 20 may comprise a plurality of personalcomputers or servers, each of which performs one or more of theseprocedures, and that one or more of these computers or servers may belocated remotely from camera 22. Imaging workstation 24 displays thereconstructed images and allows the attending healthcare worker to viewand manipulate the images.

Imaging system 10 typically customizes one or more of these proceduresat least in part responsively to imaging protocol information and/orpatient-specific information read by a communication element 30 from apatient-specific data carrier 32, such as described in InternationalApplication PCT/IL2006/000562, filed May 11, 2006, which published asPCT Publication WO 2006/129301, and/or in the other patent applications,patent application publications, and/or patents incorporated herein byreference.

For some applications, camera 22 utilizes techniques described in theabove-mentioned PCT Publications WO 06/051531 and/or WO 05/119025,and/or in the other patent applications, patent applicationpublications, and/or patents incorporated herein by reference.

In an embodiment of the present invention, camera 22 comprises aplurality of detectors 40, each of which is coupled to a respectiveangular orientator 42. Each of the detectors comprises a plurality ofgamma ray sensors, such as a pixelated CZT array, and a collimator. Forexample, the array may include 16×64 pixels. Control unit 20 drives,typically separately, each of the orientators to orient its respectivedetector in a plurality of orientations with respect to a region ofinterest (ROI). Control unit 20 produces a SPECT image from a pluralityof radiation acquisitions acquired with the detectors in differentrelative orientations.

In an embodiment of the present invention, imaging system 10 isconfigured to perform imaging of the subject while the subject is in asubstantially upright position. For example, the system may comprise achair. Performing the imaging while the subject is upright generallyreduces interference caused by photon emissions from the liver, whichbecomes quickly contaminated after teboroxime administration. Uprightpositioning causes the liver to be positioned further from the heartthan the liver is when the subject is recumbent, because of the lowerposition of the diaphragm. Alternatively, imaging system 10 isconfigured to perform imaging while the subject is recumbent, orpartially upright.

In an embodiment of the present invention, imaging system 10 isconfigured to perform ROI-centric imaging of the heart, such as by usingtechniques described in PCT/IL2005/001173, filed Nov. 9, 2005 , whichpublished as PCT Publication WO 2006/051531, and/or in other patentapplications and publications incorporated herein by reference.

In an embodiment of the present invention, imaging system 10 isconfigured to at least partially correct for liver contamination bymodeling the uptake of teboroxime in the liver, and removing expectedliver emissions from the detected emissions. For example, techniques maybe used that are described in the above-mentioned article by Sitek A etal.

Reference is made to FIG. 3, which is a schematic illustration of anend-to-end automated system 50 for medical imaging, in accordance withan embodiment of the present invention. System 50 comprises a pluralityof integrated elements that are configured to electronically exchangeinformation among one another. In addition to imaging system 10,described hereinabove with reference to FIG. 2, the elements include anautomated radiopharmaceutical dispensing system 52 (describedhereinbelow with reference to FIG. 5), a portable information-bearingradiopharmaceutical agent container 54, portable patient-specific datacarrier 32, and an automated administration system 56 (describedhereinbelow with reference to FIG. 4). Typically, a data carrier 58 isphysically coupled to container 54. The systems perform their respectiveautomated functions at least in part responsively to the exchangedinformation. The elements typically authenticate one another via theexchanged information, in order to ensure that only authorized elementsparticipate in the system, and that only authorized and appropriatefunctions are performed. System typically utilizes technique describedin International Application PCT/IL2006/000562, filed May 11, 2006,and/or in the other patent applications, patent applicationpublications, and/or patents incorporated herein by reference.

System 50 assigns a portable patient-specific data carrier 32 to eachpatient, and transmits information to data carrier 32, including atleast a patient identifier (typically, the patient's identification codeand/or name), and the assigned administration and imaging protocols.Additional patient data parameters recorded may include physiologicaldata such as girth, height and weight. Prior to administration of aradiolabeled radiopharmaceutical agent stored in agent container 54,administration system 56 authenticates container 54 and verifies theidentity of the patient, using information provided by patient-specificdata carrier 32 and container data carrier 58. Typically, all or aportion of the information used for such verification is encrypted, andadministration system 56 decrypts the information during theverification procedure.

Overview of Automated Administration System

Reference is made to FIG. 4, which is a schematic illustration ofautomated administration system 56, in accordance with an embodiment ofthe present invention. Administration system 56 comprises a control unit60, at least one communication element 30, and, for some applications,an automated administration device 62. Typically, control unit 60comprises a standard personal computer or server with appropriatememory, communication interfaces and software for carrying out thefunctions prescribed by relevant embodiments of the present invention.This software may be downloaded to the control unit in electronic formover a network, for example, or it may alternatively be supplied ontangible media, such as CD-ROM. Typically, radiopharmaceutical agentcontainer 54 comprises a cartridge into which a syringe containing theagent(s) has been placed.

Upon authenticating container 54, verifying the identity of the patient,and performing additional verifications, control unit 60 generates anadministration signal that triggers administration to the patient of thelabeled radiopharmaceutical agent(s) stored in container 54. Forapplications in which administration system 56 comprises automatedadministration device 62, container 54 is operatively coupled to device62, and the signal drives administration device 62 to administer thelabeled radiopharmaceutical agent(s) stored therein to the patient.Automated administration device 62 is configured to perform intravenous(IV) injection, intramuscular (IM) injection, subcutaneous injection,transdermal application, oral administration, nasal administration,inhalation, transcervical application, transrectal administration, oranother type of administration known in the art. (It is to be understoodthat although the administration signal triggers administration of theagent, for some applications automated administration device 62 does notadminister the agent until a healthcare worker provides a finalauthorization to do so, such as to comply with regulatory safetyrequirements.) For applications in which administration system 56 doesnot comprise automated administration device 62, the administrationsignal triggers administration of the agent by instructing a healthcareworker to manually administer the agent to the patient.

For some applications, based on administration protocol informationreceived from data carrier 58 of radiopharmaceutical agent container 54and/or patient-specific data carrier 32, control unit 60 customizes theadministration of the labeled radiopharmaceutical agent(s) contained inagent container 54, typically using information provided bypatient-specific data carrier 32 or data carrier 58 of container 54. Forexample, system 56 may customize a time-dependent administration profileof the labeled radiopharmaceutical agent, such as a rate ofadministration. Alternatively or additionally, system 56 may administerless than the entire dose of the labeled radiopharmaceutical agent,e.g., based on feedback from imaging system 10 during an imagingprocedure. For some applications, administration system 56 administers aplurality of labeled radiopharmaceutical agents, either sequentially orpremixed together within a single agent container 54 (i.e., as acocktail).

In an embodiment of the present invention, automated administrationdevice 62 is configured to use pre-packaged ready-to-useradiopharmaceutical agent containers 54, into which are insertedsyringes pre-filled with one or more radiopharmaceutical agents, such asteboroxime. The pre-filled syringes are typically distributed as a kit,which, for some applications, includes additional pharmacological agents(such as pharmacological stress agents, dipyridmole, adenosine,persantine, A2A, nitroglycerin, another vasodilator, or anotherimaging-enhancing imaging product). Several embodiments ofradiopharmaceutical agent container 54 are described in InternationalApplication PCT/IL2006/000562, filed May 11, 2006, such as withreference to FIGS. 9A-H thereof.

For some applications, administration system 56 uses techniquesdescribed in International Application PCT/IL2006/000562, filed May 11,2006, which published as PCT Publication WO 06/129301, which is assignedto the assignee of the present application and is incorporated herein byreference, and/or in U.S. patent application Ser. No. 11/750,057, filedMay 17, 2007, which published as U.S. Patent Application Publication2008/0131362, and is assigned to the assignee of the present applicationand is incorporated herein by reference, and/or in the other patentapplications, patent application publications, and/or patentsincorporated herein by reference.

In some embodiments of the present invention, protocol information fromany of the protocols described is stored in at least one portablecomputer-communicatable data carrier associated with agent container 54,such as in patient-specific data carrier 32 and/or in container datacarrier 58.

Overview of Dispensing System

Reference is made to FIG. 5, which is a schematic illustration ofautomated radiopharmaceutical dispensing system 52, in accordance withan embodiment of the present invention. System 52 comprises a controlunit 500, at least one robot 502, and at least one communication element504, which, for some applications, is coupled to robot 502. Control unit500 typically comprises a conventional personal computer running aconventional operating system, such as Windows XP, with appropriatememory, communication interfaces and software for carrying out thefunctions described herein. This software may be downloaded to thecontrol unit in electronic form over a network, for example, or it mayalternatively be supplied on tangible media, such as CD-ROM. Controlunit 500 is in communication with other elements of system 10. Thecontrol unit notifies appropriate elements of the system upon successfulcompletion of dispensing of a dose.

At least one radiolabeled mother vial 104 is placed in a shielded vialscomplex 505 of dispensing system 52. Control unit 500 authenticates themother vial, typically by actuating communication element 504 to readauthentication information stored in a mother vial data carrier 106associated with mother vial 104. Upon successful authentication, controlunit 500 actuates communication element 504 to readradiopharmaceutical-related information from data carrier 106 of themother vial, including the radiopharmaceutical agent type, isotope type,batch, lot, radiochemical purity (RCP), preparation time, and half-lifeinformation. Dispensing system 52 assays the radioactivity per unitvolume of the labeled radiopharmaceutical agent contained in the mothervial. Robot 502 picks up an empty syringe 506 from a syringe tray 508,draws a predetermined amount of solution from mother vial 104, andbrings the syringe to a dose calibrator 510. The syringe used for theassaying is typically discarded into a waste container 512. Typically,robot 502 brings the mother vial to a weighing station 507 forverification that the vial contains the indicated solution volume.

Dispensing system 52 receives a patient-specific dose request for atleast one specific labeled radiopharmaceutical agent, having a specificdose, radioactivity, and solution volume. Responsively to thepatient-specific dose request, the dispensing system typicallycustomizes the prepared dose. To fill the request, control unit 500calculates a required volume of the labeled radiopharmaceutical agentand a required volume of saline solution for dilution, if any. Toperform this calculation, control unit 500 uses (a) information readfrom data carrier 106 (such as the half-life of the labeling isotope ofthe labeled radiopharmaceutical agent), and (b) the assayedradioactivity of the labeled radiopharmaceutical agent.

For some applications, control unit 500 authenticates mother viallicense information read from data carrier 106, in order to verify thata license is available for dispensing the requested dose. Dispensingproceeds only if a license is available and authenticated. The use ofsuch a license generally provides increased quality control of theimaging process, by verifying that only approved manufacturers (ordistributors) are able to provide radiopharmaceutical agents for usewith system 10. A lack of precision in any aspect of an imagingprocedure, which may result from the use of an agent that has not beentested and approved for use with system 10, often causes a deteriorationof the resultant image quality and/or ability to make accurate and/orquantitative diagnoses.

Control unit 500 actuates robot 502 to pick up an emptyradiopharmaceutical agent container 54 from tray 508. Typically, but notnecessarily, container 54 comprises a syringe. Container 54 has coupledthereto a data carrier 58. For some applications, syringes 506 andcontainers 54 are stored in a single tray, as shown in FIG. 5, while forother applications, they are stored in separate trays. Robot 502typically authenticates container 54, typically by actuatingcommunication element 504 to read authentication information stored indata carrier 58.

Robot 502 removes the needle cap from container 54, turns the containerover, and brings container 54 to the appropriate mother vial 104. Therobot actuates the container to draw the calculated volume of labeledradiopharmaceutical agent from the mother vial, typically by insertingthe needle of container 54 through a membrane of mother vial 104, andwithdrawing a plunger of container 54 until the desired volume of agenthas been drawn from the mother vial. The robot typically brings thesyringe to dose calibrator 510 for quality control assaying ofradioactivity. If necessary, robot 502 brings container 54 to a salinevial, and actuates the container to draw the required volume of salinesolution into the container. Robot 502 replaces the needle cap on thecontainer, and turns the container over. Alternatively, saline solutionis drawn prior to drawing the labeled radiopharmaceutical agent frommother vial 104. For some applications, a needle of the container 54 ischanged between drawings.

For dispensing a cocktail of labeled radiopharmaceutical agents, eachhaving a respective dose, robot 502 repeats these steps for a pluralityof mother vials 104, typically changing the needle of container 54between drawings. During dispensing of such a cocktail, robot 502typically draws first from the mother vial containing the lower orlowest radiation labeled radiopharmaceutical agent, such as to reduceany effect the assaying of the first agent may have on the assaying ofthe subsequent agent(s).

System 52 typically performs a quality control check on the dispensedradiopharmaceutical solution to confirm that the solution contains thedesired dose(s) of the radiopharmaceutical agent(s) and radioactivitylevel.

Control unit 500 activates communication element 504 to writeradiopharmaceutical information to data carrier 58 of container 54. Forsome applications, the data carrier is coupled to the container prior toplacement of the container in dispensing system 52, while for otherapplications, robot 502 couples a data carrier to each container duringor after the dispensing process.

Robot 502 brings the filled container to a shield body tray 530, andinserts the container into a container shield 532. The robot picks up ashield cap 534 from a shield cap tray 536, and secures it to containershield 532. For some applications, data carrier 58 is coupled to shield532 or cap 534, rather than directly to container 54. Alternatively,separate data carriers 58 are coupled to the container and the shield orcap.

In an embodiment of the present invention, dispensing system 52comprises a print area 540, at which dispensing system 52 prints andattaches at least one conventional label to container 54, shield 532,and/or cap 534, in order to comply with regulatory labelingrequirements. The dispensing system typically prints yet anotherconventional label for placement on a basket that holds a plurality ofcontainers 54 for transport within or between healthcare facilities.

After the dispensing of container 54 has been completed, robot 502brings the container to a completed container tray (tray not shown inthe figure).

For some applications, dispensing system 52 uses techniques described inInternational Application PCT/IL2006/000562, filed May 11, 2006, and/orin the other patent applications, patent application publications,and/or patents incorporated herein by reference.

Clinically-Valuable Teboroxime Images

In an embodiment of the present invention, imaging system 10 produces a“clinically-valuable image” of a cardiac region of interest (ROI) uponadministration of teboroxime at a dose of between about 6 and about 50mCi, e.g., between about 6 and about 30 mCi, such as between about 6 andabout 15 mCi, e.g., between about 8 and about 12 mCi. For someapplications, such image is acquired during a time period having aduration of no more than 5 minutes, such as no more than about 3minutes, or no more than about 2.5 minutes, e.g., about 2 minutes,commencing between 1 and 3 minutes after administration of theteboroxime. Completion of image acquisition thus occurs before theconcentration of teboroxime in the liver reaches a level thatsubstantially reduces the accuracy of the imaging, as shown in FIG. 1.For example, the completion of image acquisition may occur less than 6minutes after completion of the administration, such as less than 5minutes after completion of the administration, e.g., less than 4minutes after completion of the administration.

For some applications, imaging system 10 produces a clinically-valuableimage of a cardiac ROI upon administration of the teboroxime at a givendose and during a time period having a given duration, wherein theproduct of the dose and the duration is less than 50 mCi*minutes, e.g.,less than 30, 20, 10, or 5 mCi*minutes.

In an embodiment of the present invention, imaging system 10 performs adynamic imaging study by acquiring a plurality of clinically-valuableimages during the time period, such as at least 18 images, e.g., atleast 24 images. Typically, the time resolution of such dynamic imagesis between about 5 and about 40 seconds per full scan of the heart.

In an embodiment of the present invention, imaging system 10 performs adynamic imaging study with frames having a duration of less than aboutone minute, e.g., less than or equal to about 40 seconds, or less thanor equal to about 30 seconds.

A “clinically-valuable image,” as used in the present application, is animage of the cardiac ROI containing a radiopharmaceutical, such as theteboroxime (or teboroxime in combination with additionalradiopharmaceutical agent(s) or substances, such as describedhereinbelow with reference to FIGS. 6B, 6C, 6H, 6I, and 6J), which imagefulfills one or more of the following criteria:

-   -   the image is generated according to a protocol, including at the        radiopharmaceutical dose specified by the protocol, using a        high-definition SPECT camera, for example, camera 22 of imaging        system 10, described hereinabove with reference to FIG. 2, which        camera, during the imaging of the cardiac ROI, is capable of        acquiring at least one of 5000 photons emitted from the ROI        during the image acquisition procedure, such as at least one of        4000, 3000, 2500, 2000, 1500, 1200, 1000, 800, 600, 400, 200,        100, or 50 photons emitted from the ROI. In one particular        embodiment, the camera is capable of acquiring at least one of        2000 photons emitted from the ROI during the image acquisition        procedure;    -   the image is generated according to a protocol, including at the        radiopharmaceutical dose and image acquisition duration        specified by the protocol, using a high-definition SPECT camera,        for example, camera 22, which, during the imaging of the ROI, is        capable of acquiring at least 200,000 photons, such as at least        500,000, 1,000,000, 2,000,000, 3,000,000, 4,000,000, 5,000,000,        8,000,000, or 10,000,000 photons, emitted from a portion of the        ROI, which portion has a volume of no more than 500 cc, such as        a volume of no more than 500 cc, 400 cc, 300 cc, 200 cc, 150 cc,        100 cc, or 50 cc. In one particular embodiment, the camera is        capable of acquiring at least 1,000,000 photons emitted from a        volume of the ROI having a volume of no more than 200 cc;    -   the image has a resolution of at least 7×7×7 mm, such as at        least 6×6×6 mm, 5×5×5 mm, 4×4×4 mm, 4×3×3 mm, or 3×3×3 mm, in at        least 50% of the reconstructed volume, wherein the labeled        radiopharmaceutical agent as distributed within the ROI has a        range of emission-intensities R (which is measured as emitted        photons/unit time/volume), and wherein at least 50% of the        voxels of the reconstructed three-dimensional emission-intensity        image of the ROI have inaccuracies of less than 30% of range R,        such as less than 25%, 20%, 15%, 10%, 5%, 2%, 1%, or 0.5% of        range R. For example, the agent may emit over a range from 0        photons/second/cc to 10^5 photons/second/cc, such that the range        R is 10^5 photons/second/cc, and at least 50% of the voxels of        the reconstructed three-dimensional intensity image of the ROI        have inaccuracies of less than 15% of range R, i.e., less than        1.5×10^4 photons/second/cc. For some applications, the study        produce a parametric image related to a physiological process        occurring in each voxel. In one particular embodiment, the image        has a resolution of at least 5×5×5 mm, and at least 50% of the        voxels have inaccuracies of less than 15% of range R;    -   the image is generated according to a protocol, including at the        radiopharmaceutical dose and image acquisition duration        specified by the protocol, and the image has a resolution of at        least 7×7×7 mm, such as at least 6×6×6 mm, 5×5×5 mm, 4×4×4 mm,        4×3×3 mm, or 3×3×3 mm, in at least 50% of the reconstructed        volume, wherein the labeled radiopharmaceutical agent as        distributed within the ROI has a range of emission-intensities R        (which is measured as emitted photons/unit time/volume), and        wherein at least 50% of the voxels of the reconstructed        three-dimensional emission-intensity image of the ROI have        inaccuracies of less than 30% of range R, such as less than 25%,        20%, 15%, 10%, 5%, 2%, 1%, or 0.5% of range R. For example, the        agent may emit over a range from 0 photons/second/cc to 10^5        photons/second/cc, such that the range R is 10^5        photons/second/cc, and at least 50% of the voxels of the        reconstructed three-dimensional intensity image of the ROI have        inaccuracies of less than 15% of range R, i.e., less than        1.5×10^4 photons/second/cc. For some applications, the study        produces a parametric image related to a physiological process        occurring in each voxel. In one particular embodiment, the image        has a resolution of at least 5×5×5 mm, and at least 50% of the        voxels have inaccuracies of less than 15% of range R;    -   the image has a resolution of at least 20×20×20 mm, such as at        least 15×15×15 mm, 10×10×10 mm, 7×7×7 mm, 5×5×5 mm, 4×4×4 mm,        4×3×3 mm, or 3×3×3 mm, wherein values of parameters of a        physiological process modeled by a parametric representation        have a range of physiological parameter values R, and wherein at        least 50% of the voxels of the reconstructed parametric        three-dimensional image have inaccuracies less than 100% of        range R, such as less than 70%, 50%, 40%, 30%, 25%, 20%, 15%,        10%, 5%, 2%, 1%, or 0.5% of range R. For example, the        physiological process may include blood flow, the values of the        parameters of the physiological process may have a range from 0        to 100 cc/minute, such that the range R is 100 cc/minute, and at        least 50% of the voxels of the reconstructed parametric        three-dimensional image have inaccuracies less than 25% of range        R, i.e., less than 25 cc/minute. In one particular embodiment,        the image has a resolution of at least 5×5×5 mm, and at least        50% of the voxels have inaccuracies of less than 25% of range R;        and/or    -   the image is generated according to a protocol, including at the        radiopharmaceutical dose and image acquisition duration        specified by the protocol, and the image has a resolution of at        least 7×7×7 mm, such as at least 6×6×6 mm, 5×5×5 mm, 4×4×4 mm,        4×3×3 mm, or 3×3×3 mm, in at least 50% of the reconstructed        volume, wherein if the labeled radiopharmaceutical agent is        distributed substantially uniformly within a portion of the ROI,        which portion has an emission-intensity I+/−10% (which is        defined as emitted photons/unit time/volume), and wherein at        least 85% of the voxels of the reconstructed three-dimensional        emission-intensity image of the portion of the ROI have        inaccuracies of less than 30% of intensity I, such as less than        15%, 10%, 5%, 2%, 1%, 0.5%, 20%, or 25% of intensity I. For        example, the agent may be distributed within a volume with a        uniform emission-intensity I of 10^5 photons/second/cc, and at        least 85% of the voxels of the reconstructed three-dimensional        intensity image of the volume have inaccuracies of less than 15%        of intensity I, i.e., less than 1.5×10^4 photons/second/cc. For        some applications, the same definition may apply to a study        which produces a parametric image related to a physiological        process occurring in each voxel. In one particular embodiment,        the image has a resolution of at least 5×5×5 mm, and at least        50% of the voxels have inaccuracies of less than 15% of        intensity I.

In an embodiment of the present invention, imaging system 10 isconfigured to modify one or more scan parameters during an imagingprocedure. For example, during an early portion of an imaging procedure,the imaging system may acquire relatively low-resolution images, andduring a later portion of the procedure, the imaging system may acquirehigher-resolution images. For some applications, the system modifies theone or more parameters during the imaging procedure responsively to oneor more properties acquired during the procedure. For some applications,techniques are used that are described in above-mentioned InternationalApplication PCT/IL2006/001291, which published as PCT Publication WO2007/054935.

Reference is made to Table 1, which is a table showing humanexperimental results, measured in accordance with an embodiment of thepresent invention. This experiment was performed in order todemonstrate, in a clinical setting, the SPECT sensitivity of a novelcardiac scanner similar to SPECT imaging system 10, describedhereinabove with reference to FIG. 2. Although this experiment wasperformed with Tc99m-sestamibi, the inventors believe that similarresults would be obtained with teboroxime Tc99m, because sestamibi andteboroxime are both labeled with the same radioisotope, Tc99m.

In this experiment, three adult human volunteers were imaged both withthe novel cardiac scanner similar to SPECT imaging system 10 and aconventional gamma camera (Varicam™ gamma camera; General Electric)equipped with a Low Energy High Resolution (LEHR) collimator forcomparison of sensitivity. Conventional gamma camera images wereacquired using a 180 degree elliptical orbit and 23.4 seconds/stop for32 stops (mean acquisition time of 12.5 minutes). The imaging with thenovel cardiac scanner had an acquisition time of two minutes.Counts/minute in the myocardium for both the novel cardiac scanner andthe conventional gamma camera acquisitions were determined by analysisof raw data images on the Xeleris workstation (GE Medical, computermodel XW6200, Xeleris ver.1.1324). The calculation of counts from themyocardium was made by summing the number of counts collected from theleft ventricle only, and correcting for radioactive decay during thetime delay between imaging with the conventional camera and imaging withthe novel cardiac scanner. The sensitivity in millions of counts(MC)/minute was calculated by dividing the number of counts from themyocardium by the scan duration in minutes. The sensitivity gain factorwas defined as the ratio between the sensitivity of the novel cardiacscanner and that of the conventional gamma camera.

As can be seen in Table 1, the novel cardiac scanner had a sensitivitygain factor in the three subjects ranging from 7.0 to 10.5, for anaverage sensitivity gain of 8.6. As described hereinabove, suchincreased sensitivity enables many of the novel protocols andradiopharmaceutical formulations described in the present application.

TABLE 1 Patient 1 Patient 2 Patient 3 Dose 28.29 mCi 23.4 mCi 26.5 mCiImaging duration (minutes) 12.5 2 12.5 2 12.5 2 Total study counts(million counts [MC]) Before decay correction 17.08 2.06 16.15 1.9614.26 After decay correction n/a 2.68 n/a 2.61 n/a 2.71 Myocardiumcounts Before decay correction 1.70 1.46 1.43 1.37 1.18 After decaycorrection n/a 1.90 n/a 1.83 n/a 1.98 Myocardium counts % 9.5% 71.0%8.9% 71.1% 8.3% 73.1% total counts Myocardium sensitivity 0.136 0.950.11 0.92 0.095 0.99 after decay correction (MC/min) Sensitivity gainfactor 1.0 7.0 1.0 8.4 1.0 10.5

A dynamic study simulation was performed in order to demonstrate theSPECT sensitivity of SPECT imaging system 10, described hereinabove withreference to FIG. 2. A digital NURBS-based Cardiac-Torso (NCAT) phantomhaving internal organs was used. The dimensions of the internal organsare based on CT information from a real patient, such that the phantomis realistic. The simulation modeled an injected dose of 22.5 mCi ofteboroxime. The total scan time was 4 minutes, which included 2410-second frames. The number of counts measured in the left ventricle atthe time of maximal uptake during a 10-second frame was calculated to be280,000 photons.

Reference is made to FIG. 8, which is a graph showing input curves, inaccordance with an embodiment of the present invention. These inputcurves are taken from Reutter et al., “Accuracy and precision ofcompartmental model parameters obtained from directly estimated dynamicSPECT time-activity curves,” 2002 IEEE Nuclear Science Symposium, pp.1584-1588, which is incorporated herein by reference. The phantom wasconfigured such that the dynamics of the tracer uptake and washoutmimicked that of teboroxime, using the input curves shown in FIG. 8.

FIG. 9 shows a series of mid-ventricular slice images produced by thesimulation during the first four minutes after the simulated teboroximeinjection, in accordance with an embodiment of the present invention.Each image represents a single 10-second frame. The upper row of imagesare short axis (SA) views, while the lower row of images are horizontallong axis (HLA) views. As can be seen in the series of images, theintense blood pool activity at the center of the heart chambersgradually clears while the myocardial uptake gradually intensifies.

Further supporting evidence for the greater sensitivity of embodimentsof imaging system 10 compared to conventional SPECT imaging systems isprovided in the above-mentioned International ApplicationPCT/IL2005/001173 (see, for example, the Summary of the Inventionsection thereof).

Low-Dose Teboroxime Kits and Doses

DEFINITIONS

Listed below are definitions of the terms used to describe the^(99m)Tc-containing species that constitute part of some embodiments ofthe present invention. These definitions apply to the terms as they areused throughout the specification (unless they are otherwise limited inspecific instances) either individually or as part of a larger group.

The terms “alkyl” and “alkoxy” refer to both straight and branched chaingroups, e.g. methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,isobutyl, t-butyl, straight and branched pentyl, straight and branchedhexyl, straight and branched heptyl, straight and branched octyl,straight and branched nonyl, and straight and branched decyl, as well asthe alkoxy analogues thereof.

The term “alkenyl” refers to both straight and branched chain groupshaving one or more double bonds, e.g. ethenyl, propenyl, 1-, 2- and3-butenyl, straight and branched pentenyl, straight and branchedhexenyl, straight and branched heptenyl, straight and branched octenyl,straight and branched nonenyl, and straight and branched decenyl.

The term “aryl” refers to phenyl and substituted phenyl, such as phenylsubstituted with 1, 2 or 3 alkyl, haloalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, alkoxy, alkoxyalkyl, halogen, amino,hydroxy, or formyl groups. Additional exemplary aryl groups for theinstance wherein R₃ is aryl include3-(5-dimethylamino-1-naphthalenesulfonylamino)phenyl,3-[4-[3′-phenyl-2′-pyrazolin-1,1′-yl]benzenesulfonyl-amino]phenyl,3-(pyrenesulfamido)phenyl,3-[4-(4-dimethylamino-1-naphthylazo)-3-(methoxyphenyl-sulfamido)]phenyl,and 3-[4-(4-dimethylamino-1-phenylazo) phenylthioureido]phenyl.

“Cycloalkyl” and “cycloalkenyl” groups include those having 5, 6 or 7carbon atoms. The terms include those groups substituted with alkyl,alkoxy, aryl, carboxyalkyl, arylalkyl or (R₄R₅N)-alkyl groups.

The terms “halide”, “halo” and “halogen” refer to fluorine, chlorine,bromine and iodine.

The expression “5 or 6-membered nitrogen containing heterocycle” refersto all 5 and 6-membered rings containing at least one nitrogen atom.Exemplary aliphatic groups are dehydro derivatives of a compound havingthe formula

wherein m is 0 or 1 and A is O, N—R₆ or CH—R₆ wherein R₆ is hydrogen,alkyl, aryl or arylalkyl. Such groups include pyrrolidinyl, piperidinyl,morpholinyl, piperazinyl, 4-alkylpiperazinyl, 4-alkylpiperidinyl, and3-alkylpyrrolidinyl groups. Also included within the expression “5 or6-membered nitrogen containing heterocycle” are aromatic groups.Exemplary aromatic groups are pyrrolyl, imidazolyl, oxazolyl, pyrazolyl,pyridinyl, and pyrimidinyl groups. The above groups can be linked via ahetero atom or a carbon atom.

The expression “5 or 6-membered nitrogen or oxygen containingheterocycle” refers to all 5 and 6-membered rings containing at leastone nitrogen or oxygen atom. Exemplary groups are those described aboveunder the definition of the expression “5 or 6-membered nitrogencontaining heterocycle”. Additional exemplary groups are 1,4-dioxanyland furanyl.

In an embodiment of the present invention, a kit or a containercontaining a dose of a radiolabeled radiopharmaceutical agent comprisesa 99m-BATO species having a radioactivity of less than 5 mCi, such asless than or equal to 4.5 mCi, less than or equal to 4 mCi, or less thanor equal to 3 mCi, e.g., between 2 and 3 mCi. Imaging system 10 is ableto produce clinically-valuable images using this kit or radiolabeledradiopharmaceutical agent. For some applications, the ingredients formaking the 99m-BATO species, other than ^(99m)Tc, are contained in afirst container, and the technetium Tc-99m is contained in a secondcontainer. For other applications, a dose of the 99m-BATO species isprepared from the ingredients and the technetium Tc-99m having theabove-mentioned radioactivity. For example, automatedradiopharmaceutical dispensing system 52, described hereinabove withreference to FIG. 5, may prepare a dose of teboroxime Tc-99m from theingredients and technetium Tc-99m stored in radiolabeled mother vial104. For some applications, such a dose is stored together withadditional doses in a single container, either in a same chamber of thecontainer, or in separate chambers of the container.

For some applications, in order to achieved a desired radioactivity atthe time of administration, the teboroxime or other 99m-BATO species isdispensed with an initial radioactivity that is greater than the desiredradioactivity at the time of administration. Such initial radioactivityis calculated based on the known half-life of the Tc-99m and an estimateof the time of administration. Such calculation is typically performedby an automated dispensing system (e.g., dispensing system 52), aradiopharmaceutical pharmacy system, or a pharmacist.

The technetium Tc-99m is typically in physiological saline.

In an embodiment of the present invention, the kit for making the99m-BATO species comprises the following lyophilized ingredients:

-   -   an anion source;    -   a boronic acid derivative, or compounds which can react in situ        to form a boronic acid derivative, having the formula

-   -   or a pharmaceutically acceptable salt thereof, wherein R₃ is        hydroxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy,        carboxyalkyl, carboxyalkenyl, hydroxyalkyl, hydroxalkenyl,        alkoxyalkyl, alkoxy-alkenyl, haloalkyl, haloalkenyl, aryl,        arylalkyl, or R₄R₅N-alkyl and R₄ and R₅ are each independently        hydrogen, alkyl, or arylalkyl, or R₄ and R₅ when taken together        with nitrogen atom to which they are attached form a 5 or        6-membered nitrogen containing heterocycle, and R₇ is hydrogen,        alkyl or aryl; and    -   at least one dioxime having the formula

-   -   or a pharmaceutically acceptable salt thereof, wherein R₁ and R₂        are each independently hydrogen, halogen, alkyl, aryl, amino or        a 5 or 6-membered nitrogen or oxygen containing heterocycle, or        together R₁ and R₂ are —(CR₈R₉)_(n)— wherein n is 3, 4, 5, or 6        and R₈ and R₉ are each independently hydrogen or alkyl;

In some embodiments, the kit contains a reducing agent, such as stannouschloride or stannous fluoride. In some embodiments, the kit contains apharmaceutically acceptable complexing agent (also sometimes referred toas a chelating agent). Examples of complexing agents arediethylenetriamine-pentaacetic acid (DTPA, also known as pentetic acid),ethylene glycol-bis(β-aminoethyl ether)-N,N′-tetraacetic acid (EGTA),ethylenediamine tetraacetic acid (EDTA), citric acid, tartaric acid,malonic acid, etc. In some embodiments, the kit contains an accelerator(catalyst) which serves to improve the radiochemical purity (i.e.,percent of the radioactivity that is in the desired chemical form) ofthe product. Examples of accelerators are the α-hydroxycarboxylic acidssuch as citric acid, tartaric acid, and malonic acid.

Thus, in an embodiment of the present invention, the kit for making the99m-BATO species comprises the following lyophilized ingredients:

-   -   5 to 15 mg sodium chloride, or sodium bromide;    -   1 to 3 mg of boronic acid derivative, or compounds which can        react in situ to form a boronic acid derivative, having the        formula

-   -   or a pharmaceutically acceptable salt thereof, wherein R₃ is        hydroxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy,        carboxyalkyl, carboxyalkenyl, hydroxyalkyl, hydroxalkenyl,        alkoxyalkyl, alkoxyalkenyl, haloalkyl, haloalkenyl, aryl,        arylalkyl, or R₄R₅N-alkyl and R₄ and R₅ are each independently        hydrogen, alkyl, or arylalkyl, or R₄ and R₅ when taken together        with nitrogen atom to which they are attached form a 5 or        6-membered nitrogen containing heterocycle, and R₇ is hydrogen,        alkyl or aryl;    -   1 to 3 mg of at least one dioxime having the formula

-   -   or a pharmaceutically acceptable salt thereof, wherein R₁ and R₂        are each independently hydrogen, halogen, alkyl, aryl, amino or        a 5 or 6-membered nitrogen or oxygen containing heterocycle, or        together R₁ and R₂ are —(CR₈R₉)_(n)— wherein n is 3, 4, 5, or 6        and R₈ and R₉ are each independently hydrogen or alkyl;    -   0.03 to 0.06 mg stannous chloride;    -   1 to 3 mg pentetic acid; and    -   8 to 10 mg citric acid.

In an embodiment of the present invention, the kit comprises thefollowing lyophilized ingredients:

-   -   1 to 3 mg cyclohexanedione dioxime;    -   1 to 3 mg methyl boronic acid;    -   1 to 3 mg pentetic acid;    -   8 to 10 mg citric acid;    -   5 to 10 mg sodium chloride; and    -   0.030 to 0.060 mg stannous chloride (SnCl₂); and

For some applications, the kit additionally comprises 30 to 50 mghydroxypropyl gamma cyclodextrin, which is typically contained in thecontainer containing the non-technetium ingredients.

For some applications, the dioxime is selected from the group consistingof:

-   -   dimethyl glyoxime,    -   1,2-cyclohexanedione dioxime,    -   1,2-ethanedione dioxime,    -   α-furyldioxime,    -   1,2-cyclopentanedione dioxime, and    -   3-methyl-1,2-cyclopentanedione dioxime.

For some applications, two or three different dioximes are used.

For some applications, the boronic acid derivative is selected from thegroup consisting of:

-   -   B-alkyl,    -   B-alkoxy,    -   B-benzyl and    -   B-cycloalkyl.

For some applications, the technetium Tc-99m, when added to the otheringredients, forms a complex therewith, said complex selected from thegroup consisting of:

-   -   ^(99m)Tc (chlorine) (dimethyl glyoxime)₃ methoxy boron;    -   ^(99m)Tc (chlorine) (dimethyl glyoxime)₃ hydroxy boron;    -   ^(99m)Tc (chlorine) (dimethyl glyoxime)₃ ethoxy boron;    -   ^(99m)Tc (chlorine) (dimethyl glyoxime)₃ propyloxy boron;    -   ^(99m)Tc (chlorine) (dimethyl glyoxime)₃ hexyloxy boron;    -   ^(99m)Tc (chlorine) (dimethyl glyoxime)₃ 1-methylpropyl boron;    -   ^(99m)Tc (bromine) (dimethyl glyoxime)₃ butyl boron;    -   ^(99m)Tc (iodine) (dimethyl glyoxime)₃ butyl boron;    -   ^(99m)Tc (fluorine) (dimethyl glyoxime)₃ butyl boron;    -   ^(99m)Tc (chlorine) (dimethyl glyoxime)₃ 3-(4-morpholinyl)propyl        boron;    -   ^(99m)Tc (chlorine) (dimethyl glyoxime)₃ 2-phenylethyl boron;    -   ^(99m)Tc (chlorine) (1,2-cyclohexanedione dioxime)₃ methyl        boron; and    -   ^(99m)Tc (chlorine) (dimethyl glyoxime)₃ 4-formylphenyl boron.

In an embodiment of the present invention, a boronic acid adduct oftechnetium-99m dioxime complexes is provided, having the formula^(99m)TcX(Y)₃Z,

wherein

X is an anion;

Y, which in each instance is independently chosen, is a vicinal dioximehaving the formula

or a pharmaceutically acceptable salt thereof, wherein R₁ and R₂ areeach independently hydrogen, halogen, alkyl, aryl, amino or a 5 or6-membered nitrogen or oxygen containing heterocycle, or together R₁ andR₂ are —(CR₈R₉)_(n)— wherein n is 3, 4, 5 or 6 and R₈ and R₉ are eachindependently hydrogen or alkyl; and

Z is a boron derivative of the formulaB—R₃

wherein R₃ is hydroxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy,carboxyalkyl, carboxyalkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl,alkoxyalkenyl, haloalkyl, haloalkenyl, aryl, arylalkyl or (R₄R₅N)-alkyland R₄ and R₅ are each independently hydrogen, alkyl, or arylalkyl, orR₄ and R₅ when taken together with the nitrogen atom to which they areattached form a 5 or 6-membered nitrogen containing heterocycle, and

wherein the ^(99m)Tc has a radioactivity of less than 5 mCi. In thoseembodiments of the present invention which are pharmaceutical ordiagnostic compositions, the compositions comprise a complex of theformula ^(99m)TcX(Y)₃Z as defined above, wherein the total amount of^(99m)Tc radioactivity present in that portion of the formulation whichis to be administered to a patient is less than 5 mCi.

For some applications, X is a halide.

For some applications, X is chloride or bromide.

For some applications, X is chloride.

For some applications, Y is dimethyl glyoxime, 1,2-cyclohexanedionedioxime, 1,2-ethanedione dioxime, α-furyldioxime, 1,2-cyclopentanedionedioxime, or 3-methyl-1,2-cyclopentanedione dioxime.

For some applications, Y is dimethyl glyoxime

For some applications, Y is 1,2-cyclohexanedione dioxime.

For some applications, Y is 1,2-ethanedione dioxime.

For some applications, Y is α-furyldioxime.

In some applications, the BATO species contains two or three differentdioximes Y.

For some applications, the boron derivative Z is B-alkyl.

For some applications, the boron derivative Z is B-alkoxy.

For some applications, the boron derivative Z is B-benzyl.

For some applications, the boron derivative Z is B-cycloalkyl.

For some applications, the boronic acid adduct is ^(99m)Tc(chlorine)(1,2-cyclohexanedione dioxime)₃ methyl boron.

For some applications, the boronic acid adduct is ^(99m)Tc(chlorine)(dimethylglyoxime)₃ 1-methylpropyl boron.

For some applications, the boronic acid adduct is ^(99m)Tc(chlorine)(dimethylglyoxime)₃ 4-methylphenyl boron.

For some applications, the boronic acid adduct is ^(99m)Tc(chlorine)(dimethyl glyoxime)₃ cyclopentyl boron.

For some applications, the boronic acid adduct is ^(99m)Tc (chlorine)1,2-cyclohexanedione dioxime)₃ ethyl boron.

For some applications, the boronic acid adduct is ^(99m)Tc(chlorine)(dimethyl glyoxime)₃ 4-(t-butyl)phenyl boron.

For some applications, the boronic acid adduct is ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ 2-methyl-1-propyl boron.

For some applications, the boronic acid adduct is ^(99m)Tc (chlorine)(1,2-cyclohexanedione dioxime)₃ hydroxy boron.

In an embodiment of the present invention, a method comprises producingany of the above-mentioned 99m-BATO species. For some applications,producing the 99m-BATO species comprises producing the species using anautomated radiopharmaceutical dispensing system, such as dispensingsystem 52, described hereinabove with reference to FIG. 5.

Preparation of the complexes in accordance with embodiments of thisinvention can best be accomplished using technetium-99m in the form ofthe pertechnetate ion. The pertechnetate ion can be obtained fromcommercially available technetium-99m parent-daughter generators; suchtechnetium is in the +7 oxidation state. The generation of thepertechnetate ion using this type of generator is well known in the art,and is described in more detail in U.S. Pat. Nos. 3,369,121 and3,920,995, the contents of which are incorporated herein by reference.These generators are usually eluted with saline solution and thepertechnetate ion is obtained as the sodium salt.

To prepare the complexes, pertechnetate ion (in the form of a salt) iscombined with a source of anion, a boronic acid derivative having theformula R₃B(OR₇)(OR₇) (IV) or a pharmaceutically acceptable saltthereof, wherein R₇ is in each instance independently hydrogen, alkyl oraryl, and a dioxime having the formula HON═CR₁CR₂═NOH (II) or apharmaceutically acceptable salt thereof.

It is possible, in some instances, to prepare a boronic acid derivativeof formula IV in situ. For example, when preparing a complex having analkoxy group attached to the boron atom, it is possible to utilize boricacid and the appropriate alkanol as reactants.

The source of the anion moiety (X) can be water or it can be an acid orsalt which dissociates to release an appropriate anion. Exemplaryanionic moieties are hydroxyl, halide, isothiocyanato (N═C═S⁽⁻⁾) andthiocyanato (S—C═N⁽⁻⁾. If the source of the anion is not water, thesource should be present in an appropriate concentration to competeeffectively with any water that may be present during the reaction. Ithas been reported that the source of anion should be present in thereaction mixture in a concentration of about 0.3 to 4.5 molar.

The boronic acid derivative of formula IV may be present in aconcentration of, e.g., about 5 to 200 millimolar. The dioxime offormula II may be present in a concentration of, e.g., about 9 to 43millimolar.

The formation of the complex proceeds best if the mixture ofpertechnetate ion, source of anion, boronic acid derivative, and dioximeis heated at about 25° C. to 150° C. for about 5 minutes to about 60minutes, preferably at about 100° C. to about 140° C. for about 5minutes to about 15 minutes. The reaction is preferably run in anaqueous medium at a pH of less than, or equal to, about 5.

The reaction mixture should also contain a reducing agent. Stannous ionis the preferred reducing agent, and can be introduced in the form of astannous salt such as a stannous halide (e.g., stannous chloride orstannous fluoride). The reducing agent should be present in aconcentration of about 1.5 micromolar to 6.6 millimolar.

Various pharmaceutically acceptable complexing agents (also known in theart as chelating agents) can be included as part of the complexingreaction. Exemplary complexing agents are diethylenetriamine-pentaaceticacid (DTPA, also known as pentetic acid), ethyleneglycol-bis(β-aminoethyl ether)-N,N′-tetraacetic acid (EGTA),ethylenediamine tetraacetic acid (EDTA), citric acid, tartaric acid,malonic acid, etc.

The complexing reaction mixture can also include an accelerator(catalyst) which serves to improve the radiochemical purity (i.e.,percent of the radioactivity that is in the desired chemical form) ofthe product. Exemplary accelerators are the α-hydroxycarboxylic acidssuch as citric acid, tartaric acid, and malonic acid. A combination ofDTPA and citric acid has been found to be preferred.

In some embodiments of the invention, the ^(99m)Tc-containing speciesmay be administered in conjunction with a hydroxypropyl gammacyclodextrin, e.g. 2-hydroxypropyl gamma cyclodextrin, in accordancewith what is disclosed in U.S. Pat. No. 6,056,941, the contents of whichare incorporated herein by reference.

Working with the technetium-99 isotope, the structure of the complexesformed has been investigated and has been reported to be:

Because of the short half-life of technetium-99m (i.e., 6.02 hours), itis generally necessary to prepare the complexes in accordance withembodiments this invention at, or near, the site where they are to beused. A kit having all of the components, other than the pertechnetateion, needed to prepare the boronic adducts of technetium-99m dioximecomplexes of formula I is provided in accordance with embodiments ofthis invention. Such a kit contains a source of anion, a boronic acidderivative of formula IV (or compounds which can react in situ to formsuch a derivative), or a pharmaceutically acceptable salt thereof, adioxime of formula II, or a pharmaceutically acceptable salt thereof,and a reducing agent. It may optionally contain a complexing agent.

Such kits can be formulated in aqueous solution. To optimize thestability of the kit, and to optimize the radiochemical purity of thelabeled product, the pH of the kit should be adjusted to fall within therange of about 2.0 to 5.5, e.g. 3.0, using a pharmaceutically acceptableacid or base (e.g., hydrochloric acid or sodium hydroxide). In someembodiments, the ingredients in the kit will be in lyophilized form.

The 99m-BATO complexes (^(99m)Tc-containing species) in accordance withembodiments of this invention are useful as imaging agents. Morespecifically, they are useful for imaging the myocardium and thehepatobiliary system in humans and other mammalian hosts. Thosecomplexes which are neutral at physiological pH (i.e., pH 7.4) are alsouseful for imaging the brain in humans and other mammalian hosts. [Thecharge of the complexes is determined by the sum of the charges of theorganic groups (“R₁”, “R₂” and “R₃”) attached to the boron atom and partof the dioximes.] Those complexes which contain the vicinal dioxime1,2-ethanedione dioxime are also useful for imaging the blood pool ofhumans and other mammalian hosts.

The complexes of this invention can be administered to a host by bolusintravenous injection. The size of the host, and the imaging systemused, will determine the quantity of radioactivity needed to producediagnostic images. For a human host, the quantity of radioactivityinjected will normally range from about 5 to 20 millicuries oftechnetium-99m.

The following examples are specific embodiments of ^(99m)Tc-containingspecies that may be used in accordance with embodiments of the presentinvention.

EXAMPLE 1 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ methoxy boron and^(99m)Tc (chlorine)(dimethyl glyoxime)₃ hydroxy boron

Into a 5 ml siliconized serum vial are measured 5.0 mg of dimethylglyoxime, 0.5 ml of methanol, 2.0 mg of boric acid and 0.5 mg ofstannous chloride in 5 μl of concentrated hydrochloric acid.

Sodium pertechnetate* in physiological saline (0.2 ml) is added to thevial which is then heated at 140° C. for 30 minutes yielding 6%** of the^(99m)Tc (chlorine)(dimethyl glyoxime)₃ methoxy boron as determined byHPLC (high pressure liquid chromatography). The reaction also yields^(99m)Tc (chlorine)(dimethyl glyoxime)₃ hydroxy boron. The complexes areseparated by HPLC.

EXAMPLE 2 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ ethoxy boron and^(99m)Tc (chlorine)(dimethyl glyoxime)₃ hydroxy boron

Into a 5 ml siliconized vial are measured 2.0 mg of dimethyl glyoxime in0.2 ml of ethanol, 2.0 mg of boric acid, 10 mg of citric acid in 0.1 mlof water, 100 mg of sodium chloride, 1.0 mg of diethylenetetraminepentaacetic acid, and approximately 50-60 μg of anhydrous stannouschloride in 1 μl of concentrated hydrochloric acid.

Sodium pertechnetate in physiological saline (0.5 ml) is added to thevial which is then heated at 100° C. for 5 minutes yielding 4-5% of^(99m)Tc (chlorine)(dimethyl glyoxime)₃ ethoxy boron. The reaction alsoyields ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ hydroxy boron. Thecomplexes are separated by HPLC.

EXAMPLE 3 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ propyloxy boron and 99mTc (chlorine)(dimethyl glyoxime)₃-hydroxy boron

Following the procedure of example 1, but substituting n-propanol formethanol, yields ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ ethoxy boron.The reaction also yields ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ hydroxyboron. The complexes are separated by HPLC.

EXAMPLE 4 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ butyloxy boron and^(99m)Tc (chlorine)(dimethyl glyoxime)₃ hydroxy boron

Following the procedure of example 1, but substituting n-butanol formethanol, yields 6% of ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ butyloxyboron. The reaction also yields ^(99m)Tc (chlorine)(dimethyl glyoxime)₃hydroxy boron. The complexes are separated by HPLC.

EXAMPLE 5 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ pentyloxy boron and^(99m)Tc (chlorine)(dimethyl glyoxime)₃ hydroxy boron

Following the procedure of example 1, but substituting n-pentanol formethanol, yields ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ pentyloxyboron. The reaction also yields ^(99m)Tc (chlorine)(dimethyl glyoxime)₃hydroxy boron. The complexes are separated by HPLC.

EXAMPLE 6 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ hexyloxy boron and^(99m)Tc (chlorine)(dimethyl glyoxime)₃ hydroxy boron

Following the procedure of example 1, but substituting n-hexanol formethanol, yields 8% of ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ hexyloxyboron. The reaction also yields ^(99m)Tc (chlorine)(dimethyl glyoxime)₃hydroxy boron. The complexes are separated by HPLC.

EXAMPLE 7 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ octyloxy boron and^(99m)Tc (chlorine)(dimethyl glyoxime)₃ hydroxy boron

Following the procedure of example 1, but substituting n-octanol formethanol, yields 12% ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ octyloxyboron. The reaction also yields 99 mTc (chlorine)(dimethyl glyoxime)₃hydroxy boron. The complexes are separated by HPLC.

EXAMPLE 8 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ 1-methylpropyl boron

Following the procedure of example 2, but substituting 1-methylpropaneboronic acid for boric acid, yields the title complex.

EXAMPLE 9 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ methyl boron

Into a 5 ml siliconized serum vial are measured 2.0 mg of dimethylglyoxime in 0.2 ml of ethanol, 2.0 mg of methane boronic acid, 10 mg ofcitric acid in 0.1 ml of water, 100 mg of sodium chloride, 1.0 mg ofdiethylenetetramine pentaacetic acid, and about 50-60 μg of stannouschloride in 1 μl of concentrated hydrochloric acid.

Sodium pertechnetate in physiological saline (0.5 ml) is added to thevial which is heated at 100° C. for 5 minutes yielding 80-90% of thetitle complex.

EXAMPLE 10 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ propyl boron

Following the procedure of example 9, but substituting 1-propane boronicacid for methane boronic acid, yields the title complex.

EXAMPLE 11 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ butyl boron

Following the procedure of example 9, but substituting 1-butane boronicacid for methane boronic acid, yields the title complex.

EXAMPLE 12 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ pentyl boron

Following the procedure of example 9, but substituting 1-pentane boronicacid for methane boronic acid, yields 85% of the title complex.

EXAMPLE 13 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ hexyl boron

Into a 5 ml siliconized serum vial are measured 3.0 mg of dimethylglyoxime, 20 mg of 1-hexane boronic acid, sodium pertechnetate inphysiological saline (0.2 ml) and 50 μl of saturated aqueous stannoustartrate. The vial is heated at 140° C. for 5 minutes yielding 16% ofthe title complex.

EXAMPLE 14 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ heptyl boron

Following the procedure of example 9, but substituting 8.0 mg of1-heptane boronic acid for methane boronic acid and substituting 50 μlof saturated aqueous stannous tartrate for stannous chloride inhydrochloric acid, yields 85% of the title complex.

EXAMPLE 15 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ phenyl boron

Following the procedure of example 2, but substituting benzene boronicacid for boric acid, yields 88% of the title complex.

EXAMPLE 16 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ butyl boron

Into a 5 ml siliconized serum vial are measured 1.0 mg of dimethylglyoxime in 0.1 ml of ethanol, 5.0 mg of 1-butane boronic acid in 50 μlof ethanol, 0.3 ml of saturated aqueous sodium chloride and 25 μl ofsaturated stannous pyrophosphate.

Sodium pertechnetate in physiological saline (0.1 ml) is added to thevial which is heated at 140° C. for 5 minutes yielding 70% of the titlecomplex.

EXAMPLE 17 ^(99m)Tc (bromine)(dimethyl glyoxime)₃ butyl boron

Into a 5 ml siliconized serum vial are measured 1.0 mg of dimethylglyoxime in 0.1 ml of ethanol, 5.0 mg of 1-butane boronic acid in 50 μlof ethanol, 0.3 ml of saturated aqueous potassium bromide, and 25 μl ofsaturated aqueous stannous pyrophosphate.

Sodium pertechnetate in physiological saline (0.1 ml) is added to thevial which is heated at 140° C. for 5 minutes yielding 59% of the titlecomplex.

EXAMPLE 18 ^(99m)Tc (iodine)(dimethyl glyoxime)₃ butyl boron

Into a 5 ml siliconized serum vial are measured 1.0 mg of dimethylglyoxime in 0.1 ml of ethanol, 5.0 mg of 1-butane boronic acid in 50 μlof ethanol, 0.3 ml of saturated aqueous potassium iodide, 25 μl ofsaturated aqueous stannous pyrophosphate.

Sodium pertechnetate in physiological saline (0.1 ml) is added to thevial which is heated at 140° C. for 5 minutes yielding 23% of the titlecomplex.

EXAMPLE 19 ^(99m)Tc (fluorine)(dimethyl glyoxime)₃ butyl boron

Into a 5 ml siliconized serum vial are measured 1.0 mg of dimethylglyoxime in 0.1 ml of ethanol, 5.0 mg 1-butane boronic acid in 50 μl ofethanol, 0.3 ml of saturated aqueous sodium fluoride, and 25 μl ofsaturated aqeuous stannous pyrophosphate.

Sodium pertechnetate in physiological saline (0.2 ml) is added to thevial which is heated at 140° C. for 5 minutes yielding 0.6% of the titlecomplex.

EXAMPLE 20 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ 3-aminophenyl boron

Into a 5 ml siliconized serum vial are measured 5.0 mg of dimethylglyoxime in methanol, 30 mg of 3-aminobenzene boronic acid, and 0.5 mgof stannous chloride in 5 μl of concentrated hydrochloric acid.

Sodium pertechnetate in physiological saline (0.2 ml) is added to thevial which is heated at 140° C. for 5 minutes yielding 50% of the titlecomplex.

EXAMPLE 21 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ 4-methylphenyl boron

Following the procedure of example 2, but substituting p-toluene boronicacid for boric acid, yields 88% of the title complex.

EXAMPLE 22 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃3-(1-piperidinyl)propyl boron

Into a 5 ml siliconized serum vial are measured 0.5 mg of dimethylglyoxime in 0.1 ml of ethanol 1.0 mg of 3-(1-piperidinyl)propane boronicacid monohydrochloride, 0.2 ml of saturated sodium chloride, 10 mg ofcitric acid, and 50 μl of saturated aqueous stannous pyrophosphate.

Sodium pertechnetate in physiological saline (0.2 ml) is added to thevial which is heated at 100° C. for 5 minutes yielding 75% of the titlecomplex.

EXAMPLE 23 ^(99m)Tc (bromine)(dimethyl glyoxime)₃3-(1-piperidinyl)propyl boron

Into a 5 ml siliconized serum vial are measured 1.0 mg of dimethylglyoxime in 0.1 ml of ethanol, 5.0 mg of 3-(1-piperidinyl)propaneboronic acid monohydrochloride, 0.4 ml of saturated potassium bromide,10 mg of citric acid, and 50 μl of saturated aqueous stannouspyrophosphate.

Sodium pertechnetate in physiological saline (0.2 ml) is added to thevial which is heated at 100° C. for 5 minutes yielding 13.8% of thetitle complex.

EXAMPLE 24 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃3-(4-methyl-1-piperidinyl)propyl boron

Following the procedure of example 23, but substituting 0.2 ml ofsaturated sodium chloride for potassium bromide and 5.0 mg of3-(4-methyl-1-piperidinyl)propane boronic acid monohydrochloride for3-(1-piperidinyl)propane boronic acid monohydrochloride, yields 94% ofthe title complex.

EXAMPLE 25 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃3-(4-morpholinyl)propyl boron

Following the procedure of example 23, but substituting 0.2 ml ofsaturated sodium chloride for potassium bromide and 5.0 mg of3-(4-morpholinyl)propane boronic acid monohydrochloride for3-(1-piperidinyl) propane boronic acid monohydrochloride, yields 87% ofthe title complex.

EXAMPLE 26 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃3-(4-benzylpiperidinyl) propyl boron

Following the procedure of example 23, but substituting 0.2 ml ofsaturated sodium chloride for potassium bromide and 5.0 mg of3-(4-benzyl-1-piperidinyl) propane boronic acid monohydrochloride for3-(1-piperidinyl) propane boronic acid monohydrochloride, yields thetitle complex.

EXAMPLE 27 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃3-(5-dimethylamino-1-naphthalenesulfonylamino)phenyl boron

Following the procedure of example 23, but substituting 0.2 ml ofsaturated sodium chloride for potassium bromide and 5.0 mg of3-(5-dimethylamino-1-naphthalenesulfonylamino) benzene boronic acidmonohydrochloride for 3-(1-piperidinyl) propane boronic acidmonohydrochloride, yields the title complex.

EXAMPLE 28 ^(99m)Tc (chlorine) (dimethyl glyoxime)₃3-[methyl(2-phenylethyl)amino]propyl boron

Following the procedure of example 23, but substituting 0.2 ml ofsaturated sodium chloride for potassium bromide and 5.0 mg of3-(methyl(2-phenylethyl)amino) propane boronic acid for3-(1-piperidinyl) propane boronic acid monohydrochloride, yields thetitle complex.

EXAMPLE 29 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ 4-hydroxy-1-butenylboron

Following the procedure of example 2, but substituting4-hydroxy-1-butene boronic acid for boric acid, yields the titlecompound.

EXAMPLE 30 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃(4-benzyl-1-piperidinyl) boron

Following the procedure of example 22, but substituting 5 mg of(4-benzyl-1-piperidinyl) boronic acid monohydrochloride for3-(1-piperidinyl) propane boronic acid monohydrochloride yields 83% ofthe title complex.

EXAMPLE 31 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ 4-(bromomethyl)phenylboron and ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ 4-(ethoxymethyl)phenylboron

Following the procedure of example 22, but substituting 1 mg of4-(bromomethyl)benzene boronic acid for 3-(1-piperidinyl)propane boronicacid, monohydrochloride, yields less than 5% of ^(99m)Tc(chlorine)(dimethyl glyoxime)₃ 4-(bromomethyl)phenyl boron. The reactionalso yields ^(99m)Tc (chlorine) (dimethyl glyoxime)₃4-(ethoxymethyl)phenyl boron. The complexes are separated by HPLC.

EXAMPLE 32 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ 2-phenylethyl boron

Following the procedure of example 2, but substituting 2-phenylethaneboronic acid for boric acid, yields the title complex.

EXAMPLE 33 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃4-(methoxymethyl)phenyl boron

Following the procedure of example 22, but substituting 1 mg of4-(bromomethyl)benzene boronic acid for 3-(1-piperidinyl)propane boronicacid monohydrochloride and methanol for ethanol, yields the titlecomplex.

EXAMPLE 34 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃4-(butyloxymethyl)phenyl boron

Following the procedure of example 22, but substituting 1 mg of4-(bromomethyl)benzene boronic acid for 3-(1-piperidinyl)propane boronicacid monohydrochloride and butanol for ethanol, yields the titlecomplex.

EXAMPLE 35 ^(99m)Tc (chlorine)(1,2-cycloheptanedione dioxime)₃ methylboron

Following the procedure of example 9, but substituting1,2-cycloheptenedione dioxime for dimethyl glyoxime, yields 92% of thetitle complex.

EXAMPLE 36 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ 4-[(diethylamino)methyl]phenyl boron

Following the procedure of example 2, but substituting4-(aminomethyl)benzene boronic acid monohydrochloride for boric acid,and adding 2.0 mg of diethylenetriamine pentacetic acid yields 77% ofthe title complex.

EXAMPLE 37 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ 4-(aminomethyl)phenylboron

Following the procedure of example 2, but substituting4-(aminomethyl)boronic acid monohydrochloride for4-[(diethylamino)methyl]benzene boronic acid monohydrochloride, yields81% of the title complex.

EXAMPLE 38 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ hexadecyl boron

Following the procedure of example 36, but substituting hexadecaneboronic acid for 4-[(diethylamino)methyl]benzene boronic acidmonohydrochloride, yields the title complex.

EXAMPLE 39 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ 17-octadecenoic acid,18-boron

Following the procedure of example 2, but substituting18-borono-17-octadecenoic acid for boric acid, yields 62% of the titlecomplex.

EXAMPLE 40 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ 4-formylphenyl boron

Following the procedure of example 2, but substitutingp-(benzaldehyde)boronic acid for boric acid, yields 47% of the titlecomplex.

EXAMPLE 41 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ 4-[[methyl(2-phenylethyl)amino]methyl]phenyl boron

Following the procedure of example 2, but substituting4-[[methyl(2-phenylethyl)amino]-methyl]benzene boronic acidmonohydrochloride for boric acid, yields the title complex.

EXAMPLE 42 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ 4-ethylphenyl boron

Following the procedure of example 2, but substituting 4-ethylbenzeneboronic acid for boric acid, yields the title complex.

EXAMPLE 43 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ 2,4-dimethylphenylboron

Following the procedure of example 2, but substituting2,4-dimethylbenzene boronic acid for boric acid, yields the titlecomplex.

EXAMPLE 44 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃4-[(dimethylamino)methyl]phenyl boron

Following the procedure of example 2, but substituting4-[(dimethylamino)methyl]benzene boronic acid monohydrochloride forboric acid, yields the title complex.

EXAMPLE 45 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃4-[(diisopropylamino)methyl]phenyl boron

Following the procedure of example 2, but substituting4-[(diisopropylamino)methyl]benzene boronic acid monohydrochloride forboric acid, yields the title complex.

EXAMPLE 46 ^(99m)Tc (chlorine)(1,2-cyclohexanedionedioxime)₃3-(1-piperidinyl)propyl boron

Into a 5 ml siliconized vial are measured 0.5 mg of 1,2-cyclohexanedionedioxime in 0.1 ml of ethanol, 1.0 mg of 3-(1-piperidinyl)propane boronicacid monohydrochloride, 0.2 ml of saturated sodium chloride, 10 mg ofcitric acid and 50 μl of saturated stannous pyrophosphate.

Sodium pertechnetate in physiological saline (0.2 ml) is added to thevial which is then heated at 100° C. for 5 minutes yielding 84% of thetitle complex.

EXAMPLE 47 ^(99m)Tc (chlorine)(1,2-cyclohexanedione dioxime)₃3-(4-methyl-1-piperidinyl)propyl boron

Following the procedure of example 46, but substituting3-(4-methyl-1-piperidinyl)propane boronic acid monohydrochloride for3-(1-piperidinyl)propane boronic acid monohydrochloride, yields 82% ofthe title complex.

EXAMPLE 48 ^(99m)Tc (chlorine)(1,2-cyclohexanedione dioxime)₃3-(4-morpholinyl)propyl boron

Following the procedure of example 46, but substituting3-(4-morpholinyl)propane boronic acid monohydrochloride for3-(1-piperidinyl)propane boronic acid monohydrochloride, yields 90% ofthe title complex.

EXAMPLE 49 ^(99m)Tc (chlorine)(1,2-cyclohexanedione dioxime)₃3-aminophenyl boron

Following the procedure of example 46, but substituting 3-aminobenzeneboronic acid monohydrochloride for 3-(1-piperidinyl)propane boronic acidmonohydrochloride yields 93% of the title complex.

EXAMPLE 50 ^(99m)Tc (chlorine)(1,2-cyclohexanedione dioxime)₃3-(4-phenyl-1-piperidinyl) propyl boron

Following the procedure of example 46, but substituting 5.0 mg of3-(4-phenyl-1-piperidinyl)-propane boronic acid monohydrochloride for3-(1-piperidinyl) boronic acid monohydrochloride and labeling withsodium pertechnetate in physiological saline (0.3 ml), yields 84% of thetitle complex.

EXAMPLE 51 ^(99m)Tc (bromime)(1,2-cyclohexanedione dioxime)₃3-(4-phenyl-1-piperidinyl) propyl boron

Following the procedure of example 46, but substituting 5.0 mg of3-(4-phenyl-1-piperidinyl)-propane boronic acid monohydrochloride for3-(1-piperidinyl) propane boronic acid monohydrochloride and 100 mg ofpotassium bromide for sodium chloride yields the title complex.

EXAMPLE 52 ^(99m)Tc (chlorine)(1,2-cyclohexanedione dioxime)₃ 1-butylboron

Following the procedure of example 46, but substituting 1-butane boronicacid for 3-(1-piperidinyl)propane boronic acid monohydrochloride andlabeling with sodium pertechnetate in physiological saline (0.3 ml)yields 69% of the title complex.

EXAMPLE 53 ^(99m)Tc (chlorine)(1,2-cyclohexanedione dioxime)₃3-(5-dimethylamino-1-naphthalenesulfonylamino)phenyl boron

Following the procedure of example 46, but substituting3-(5-dimethylamino-1-naphthalenesulfonylamino)benzene boronic acid for3-(1-piperidinyl)propane boronic acid monohydrochloride and labelingwith sodium pertechnetate in physiological saline (0.3 ml), yields 80%of the title complex.

EXAMPLE 54 ^(99m)Tc (chlorine)(1,2-ethanedione dioxime)₃3-(5-dimethylamino-1-naphthalenesulfonylamino)phenyl boron

Following the procedure of example 53, but substituting 1,2-ethanedionedioxime for 1,2-cyclohexanedione dioxime, yields 71% of the titlecompound.

EXAMPLE 55 ^(99m)Tc (chlorine)(1,2-cyclohexanedione dioxime)₃ methylboron

Into a 5 ml siliconized serum vial are measured 2.0 mg of1,2-cyclohexanedione dioxime in 0.2 ml of ethanol, 2.0 mg of methaneboronic acid, 10 mg of citric acid, 100 mg of sodium chloride, 1.0 mg ofdiethylenetriamine pentaacetic acid, and 50-60 μg of anhydrous stannouschloride in 1 μl of concentrated hydrochloric acid.

Sodium pertechnetate in physiological saline (0.5 ml) is added to thevial which is then heated at 100° C. for 5 minutes yielding 85% of thetitle complex.

EXAMPLE 56 ^(99m)Tc (bromine)(1,2-cyclohexanedione dioxime)₃ methylboron

Following the procedure of example 55, but substituting potassiumbromide for sodium chloride and labeling with sodium pertechnetate inphysiological saline (0.1 ml), yields the title complex.

EXAMPLE 57 ^(99m)Tc (chlorine)(1,2-cyclohexanedione dioxime)₃4-ethylphenyl boron

Following the procedure of example 55, but substituting 4-ethylbenzeneboronic acid for methane boronic acid, yields the title complex.

EXAMPLE 58 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃4-[1-(diisopropylamino) ethyl]phenyl boron

Following the procedure of example 2, but substituting4-[1-(diisopropylamino)ethyl]benzene boronic acid for boric acid, yieldsthe title complex.

EXAMPLE 59 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃4-[(isopropylamino)methyl]phenyl boron

Following the procedure of example 2, but substituting4-[(isopropylamino)methyl]benzene boronic acid monohydrochloride forboric acid, yields 8% of the title complex.

EXAMPLE 60 ^(99m)Tc (chlorine)(1,2-cyclohexanedione dioxime)₃4-methylphenyl boron

Following the procedure of example 2, but substituting 4-toluene boronicacid for boric acid and 1,2-cyclohexanedione dioxime for dimethylglyoxime, yields the title complex.

EXAMPLE 61 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ 2,4,6-trimethylphenylboron

Following the procedure of example 2, but substituting2,4,6-trimethylbenzene boronic acid for boric acid, yields the titlecomplex.

EXAMPLE 62 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ 2-methyl-1-propylboron

Following the procedure of example 2, but substituting2-methyl-1-propane boronic acid for boric acid, yields 84% of the titlecomplex.

EXAMPLE 63 ^(99m)Tc (chlorine)(1,2-cyclohexanedione dioxime)₃ 1-heptylboron

Following the procedure of example 2, but substituting 1-heptane boronicacid for boric acid and 1,2-cyclohexanedione dioxime for dimethylglyoxime, yields the title complex.

EXAMPLE 64 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ 9-carboxynonyl boron

Following the procedure of example 2, but substituting 10-boronodecanoic acid for boric acid, yields the title complex.

EXAMPLE 65 ^(99m)Tc (chlorine)(1,2-cyclohexanedione dioxime)₃2-methyl-1-propyl boron

Following the procedure of example 2, but substituting2-methyl-1-propane boronic acid for boric acid and 1,2-cyclohexanedionedioxime for dimethyl glyoxime, yield 85% of the title complex.

EXAMPLE 66 ^(99m)Tc (chlorine)(1,2-cyclohexanedione dioxime)₃ ethylboron

Following the procedure of example 2, but substituting ethane boronicacid for boric acid and 1,2-cyclohexanedione dioxime for dimethylglyoxime, yields 88% of the title complex.

EXAMPLE 67 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ ethyl boron

Following the procedure of example 2, but substituting ethane boronicacid for boric acid, yields 77% of the title complex.

EXAMPLE 68 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ 3-methylphenyl boron

Following the procedure of example 2, but substituting 3-toluene boronicacid for boric acid yields the title complex.

EXAMPLE 69 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ 2-methylphenyl boron

Following the procedure of example 2, but substituting o-toluene boronicacid for boric acid yields the title complex.

EXAMPLE 70 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ cyclopentyl boron

Following the procedure of example 2, but substituting cyclopentaneboronic acid for boric acid, yields the title complex.

EXAMPLE 71 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ 2-butyl boron

Following the procedure of example 2, but substituting 2-butane boronicacid for boric acid, yields the title complex.

EXAMPLE 72 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ 4-methoxyphenyl boron

Following the procedure of example 2, but substituting 4-methoxybenzeneboronic acid for boric acid, yields the title complex.

EXAMPLE 73 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ 4-(t-butyl)phenylboron

Following the procedure of example 2, but substituting4-(t-butane)benzene boronic acid for boric acid, yields the titlecomplex.

EXAMPLE 74 ^(99m)Tc (chlorine)(1,2-ethanedione dioxime)₃ 1-butyl boron

Following the procedure of example 2, but substituting 1-butane boronicacid for boric acid and 1,2-ethanedione dioxime for dimethyl glyoximeyields 76% of the title complex.

EXAMPLE 75 ^(99m)Tc (chlorine)(dimethyl glyoxime)₃ 4-(2-propyl)phenylboron

Following the procedure of example 2, but substituting4-(2-propane)benzene boronic acid for boric acid, yields the titlecomplex

EXAMPLE 76 ^(99m)Tc (chlorine)(1,2-cyclohexanedione dioxime)₃ hydroxyboron

Following the procedure of example 2, but substituting1,2-cyclohexanedione dioxime for dimethyl glyoxime, and omittingethanol, yields the title complex.

EXAMPLE 77 ^(99m)Tc (chlorine)(α-furyldioxime)₃ methyl boron

Following the procedure of example 2, but substituting α-furyldioximefor dimethyl glyoxime, and methane boronic acid for boric acid, yieldsthe title complex.

EXAMPLE 78 ^(99m)Tc (chlorine)(3-methyl-1,2-cyclopentanedione dioxime)₃methyl boron

Following the procedure of example 2, but substituting3-methyl-1,2-cyclopentanedione dioxime for dimethyl glyoxime and methaneboronic acid for boric acid, yields the title complex.

EXAMPLE 79 ^(99m)Tc (chlorine)(1,2-cyclopentanedione dioxime)₃ methylboron

Following the procedure of example 2, but substituting1,2-cyclopentanedione dioxime for dimethyl glyoxime, and methane boronicacid for boric acid, yields the title complex.

EXAMPLE 80 ^(99m)Tc (chlorine)(1,2-cyclohexanedionedioxime)₃,3-(1-piperidinyl)propyl boron

Into a 5 ml siliconized vial are measured 0.5 mg of 1,2-cyclohexanedionedioxime in 0.1 ml of ethanol, 1.0 mg of 3-(1-piperidinyl)propane boronicacid monohydrochloride, 0.2 ml of saturated sodium chloride, 10 mg ofcitric acid, 40 mg of hydroxypropyl gamma cyclodextrin and 50 μl ofsaturated stannous pyrophosphate.

Sodium pertechnetate Tc-99m in physiological saline (0.2 ml) is added tothis vial which is then heated at 100° C. for 5 minutes yielding 84% ofthe title complex.

The solution remains clear without containing particulate matter formore than 6 hours after preparation.

EXAMPLE 81 ^(99m)Tc (chlorine)(1,2-cyclohexanedione dioxime)₃ methylboron

Into a 5 ml serum vial are measured 2.0 mg of 1,2-cyclohexanedionedioxime, 2.0 mg of methane boronic acid, 10 mg of citric acid, 10 mg ofsodium chloride, 1.0 mg of diethylenetriamine pentaacetic acid, 45 mg ofhydroxypropyl gamma cyclodextrin, 50 micrograms of SnCl₂ and 0.5-3 μl ofconcentrated hydrochloric acid.

Sodium pertechnetate Tc-99m in physiological saline (0.5 ml) is added tothe vial which is then heated at 100° C. for 5 minutes yielding 85% ofthe title complex.

The solution remains clear without containing particulate matter formore than 6 hours after preparation.

Teboroxime Imaging Protocols

Reference is made to FIGS. 6A-L, which are timelines illustratingteboroxime imaging protocols, in accordance with respective embodimentsof the present invention. These protocols take advantage of thehigh-speed and high-resolution capabilities of imaging system 10. Theseprotocols are typically implemented using an automated administrationsystem, such as automated administration system 56, describedhereinabove with reference to FIG. 4. Such automated administration istypically performed while the patient is positioned at the imagingsystem. Alternatively, these protocols are performed using manualadministration, or a combination of automated and manual administration.These protocols are typically used to produce quantitative results, suchas quantitative measures of flow of perfusion agents, and/or thepercentage of the myocardium that is ischemic for a metabolic agent.

In respective embodiments of the present invention, the protocolsdescribed herein, including hereinbelow with reference to FIGS. 6A-L,are used to produce “clinically-valuable images,” as definedhereinabove.

FIG. 6A is a timeline illustrating an ultra-fast teboroximerest/teboroxime pharmacological stress protocol, in accordance with anembodiment of the present invention. The protocol begins with theinjection of teboroxime while the patient is at rest, and typicallyalready positioned in the imaging system. The dose of this firstinjection is typically less than about 15 mCi, such as between about 6and about 15 mCi, such as between about 8 and about 12 mCi, e.g.,between about 9 and about 11 mCi. Alternatively, the dose is less than10 mCi, e.g., less than 5 mCi. (It is noted that the injectionstypically take only several seconds, but are shown with slightly longerdurations in the figures for clarity of illustration.) Rest imaging isperformed beginning at between about 1.5 and about 3 minutes afterinjection, such as between about 1.75 and about 2.25 minutes (e.g., atabout 2 minutes) after injection. The duration of the imaging istypically between about 2 and about 4 minutes, e.g., about 3 minutes.

For some applications, physical (e.g., exercise) or pharmacologicalstress is applied, such as by infusion of adenosine or persantine,beginning at about 1 to about 3 minutes after the completion of the restimaging, e.g., at about 2 minutes after the completion of the restimaging, and/or at about 6 to about 8 minutes after the initialteboroxime injection, e.g., at about 7 minutes. The infusion istypically has a dose of between about 120 μg/kg/min and about 160μg/kg/min, e.g., about 140 μg/kg/min; this dose is also typically usedfor adenosine infusion in the protocols described hereinbelow, unlessotherwise specified therein. The infusion typically has a duration ofbetween about 3 and about 5 minutes, e.g., about 4 minutes. A stressinjection of teboroxime is performed, typically between about 1 andabout 3 minutes after commencement of the infusion, e.g., about 2minutes after commencement. The stress injection typically has a dosegreater than about 15 mCi, such as between about 20 and about 40 mCi,e.g., between about 25 and about 35 mCi, or between about 30 and 35 mCi.Stress imaging is performed, typically upon completion of the stressinfusion (e.g., at about 11 minutes from the first teboroxime injection)or soon thereafter, and typically with a duration of between about 3 andabout 5 minutes, e.g., about 4 minutes.

This protocol enables the quick performance of a myocardial perfusionstudy (in about 15 minutes), which is convenient for the patient, andallows high throughput for the imaging facility. This protocol takesadvantage of the narrow window of opportunity provided by the teboroximeuptake curve, i.e., after lung clearance at about 2 minutes afterinjection, and prior to substantial liver uptake beginning at about 5minutes after injection. As mentioned above, this protocol is typicallyimplemented using an automated administration system, such as automatedadministration system 56, described hereinabove with reference to FIG.4. Such automated administration is typically performed while thepatient is positioned at the imaging system. Such automation isconvenient for the technician, the physician, and the patient, becausethe entire procedure is completed in about 15 minutes without thepatient having to leave the imaging system. Such automation alsosubstantially reduces the likelihood of error in administration.

In an embodiment of the present invention, an ultra-fastteboroxime/teboroxime protocol is provided, that is similar to theprotocol described above with reference to FIG. 6A, except that thestress phase is performed before the rest phase. For some applications,the dose of teboroxime administered during the stress phase is betweenabout 1 and about 5 mCi, between about 5 and about 15 mCi, between about15 and about 25 mCi, between about 25 and about 30 mCi, or greater thanabout 30 mCi. For some applications, the dose of teboroxime administeredduring the rest phase is between about 1 and about 5 mCi, between about5 and about 15 mCi, between about 15 and about 25 mCi, between about 25and about 30 mCi, or greater than about 30 mCi.

In some embodiments of the present invention, combinationteboroxime/thallium protocols are provided.

FIG. 6B is a timeline illustrating an ultra-fast thalliumrest/teboroxime pharmacological stress protocol, in accordance with anembodiment of the present invention. The protocol begins with theinjection of thallium while the patient is at rest. The dose of thisfirst injection is typically between about 2 and about 5 mCi, such asbetween about 3 and about 4 mCi. Beginning at between about 4 and about6 minutes after injection, e.g., at about 5 minutes after injection,rest imaging is performed. The duration of the imaging is typicallybetween about 1 and about 3 minutes, e.g., about 2 minutes.

Pharmacological stress is applied, such as by infusion of adenosine orpersantine, beginning at about 1 to about 3 minutes after the completionof the rest imaging, e.g., at about 2 minutes after the completion ofthe rest imaging, and/or at about 8 to about 10 minutes after theinitial teboroxime injection, e.g., at about 9 minutes. The infusiontypically has a duration of between about 3 and about 5 minutes, e.g.,about 4 minutes. A stress injection of teboroxime is performed,typically between about 1 and about 3 minutes after commencement of theinfusion, e.g., about 2 minutes after commencement. The stress injectiontypically has a dose of between about 20 and about 40 mCi, e.g., betweenabout 25 and about 35 mCi. Stress imaging is performed, typically uponcompletion of the stress infusion (e.g., at about 13 minutes from thethallium injection) or soon thereafter, and typically with a duration ofbetween about 3 and about 5 minutes, e.g., about 4 minutes.

This protocol enables the quick performance of a myocardial perfusionstudy (in less than about 20 minutes), which is convenient for thepatient, and allows high throughput for the imaging facility. Thisprotocol takes advantage of the narrow window of opportunity provided bythe teboroxime uptake curve, i.e., after lung clearance at about 2minutes after injection, and prior to substantial liver uptake beginningat about 5 minutes after injection. As mentioned above, this protocol istypically implemented using an automated administration system, such asautomated administration system 56, described hereinabove with referenceto FIG. 4. Such automated administration is typically performed whilethe patient is positioned at the imaging system. Such automation isconvenient for the technician, the physician, and the patient, becausethe entire procedure is completed in less than about 20 minutes withoutthe patient having to leave the imaging system. Such automation alsosubstantially reduces the likelihood of error in administration.

For some applications, this protocol is used for a viability study, byadministering a vasodilator, such as nitroglycerin or isosorbidedinitrate, in conjunction with the stress teboroxime injection. Imagingtypically begins between about 2 and about 4 minutes after completion ofadministration of the vasodilator, e.g., after nitroglycerin hasdissolved sublingually.

In an embodiment of the present invention, another ultra-fast teboroximerest/thallium pharmacological stress protocol is provided. As in theprotocol described above with reference to FIG. 6B, the present protocolbegins with the injection of thallium while the patient is at rest. Thedose of this first injection is typically between about 2 and about 5mCi, such as between about 3 and about 4 mCi. The protocol then waitsuntil the level of thallium in the blood circulation fallssubstantially, typically for between about 3 and about 10 minutes afterinjection, e.g., between about 4 and about 6 minutes after injection.Unlike in the protocol described with reference to FIG. 6B, no imagingis performed at this point in the present protocol.

Physical or pharmacological stress is applied, such as by infusion ofadenosine or persantine, typically having a duration of between about 3and about 5 minutes, e.g., about 4 minutes. A stress injection ofteboroxime is performed, typically between about 1 and about 3 minutesafter commencement of the infusion, e.g., about 2 minutes aftercommencement. The stress injection typically has a dose of between about20 and about 40 mCi; e.g., between about 25 and about 35 mCi, or,alternatively, less than 30 mCi, such as less than 20 mCi, less than 10mCi, or less than 5 mCi.

The present protocol provides two techniques for performance of theimaging, typically upon completion of the stress infusion or soonthereafter:

-   -   According to a first technique, first stress imaging of the        teboroxime is performed, typically having a duration of between        about 3 and about 5 minutes, e.g., about 4 minutes. Upon        completion of the teboroxime stress imaging, at which point the        teboroxime has substantially cleared from the heart, but the        thallium has not yet substantially cleared from the heart, rest        imaging of the thallium is performed. Because of the different        energy levels of the teboroxime and the thallium, emissions from        the thallium during the imaging of the teboroxime do not        generally substantially interfere with the teboroxime imaging.        For some applications, the stress and rest imaging are performed        during a single scanning session, while for other applications,        there is a delay between the completion of the stress imaging        and the commencement of the rest imaging.    -   According to a second technique, stress imaging of the        teboroxime and rest imaging of the thallium are performed        simultaneously, utilizing the different energy levels of the two        radiopharmaceuticals.

This protocol is typically implemented using an automated administrationsystem, such as automated administration system 56, describedhereinabove with reference to FIG. 4. Such automated administration istypically performed while the patient is positioned at the imagingsystem. Such automation is convenient for the technician, the physician,and the patient, because the entire procedure is completed in about 15to 20 minutes without the patient having to leave the imaging system.Such automation also substantially reduces the likelihood of error inadministration.

In an embodiment of the present invention, yet another ultra-fastteboroxime rest/thallium pharmacological stress protocol is provided, inwhich stress imaging is performed prior to rest imaging. The protocolbegins with the application of physical or pharmacological stress, suchas by infusion of adenosine or persantine, typically having a durationof between about 3 and about 5 minutes, e.g., about 4 minutes. Ifphysical stress is used, the patient may perform the exercise prior toposition the patient at the imaging system. A stress injection ofthallium is performed, typically between about 1 and about 3 minutesafter commencement of the infusion, e.g., about 2 minutes aftercommencement. Typically, the stress thallium has a dose of between about3 and about 5 mCi, between about 1 and about 5, or less than about 1mCi, and the stress imaging has a duration of between about 3 and about5 minutes, e.g., about 4 minutes.

The protocol continues with the injection of teboroxime while thepatient is at rest, and typically already positioned in the imagingsystem. The dose of this injection is typically less than about 15 mCi,such as between about 6 and about 15 mCi, such as between about 8 andabout 12 mCi, e.g., between about 9 and about 11 mCi. Alternatively, thedose is less than 10 mCi, e.g., less than 5 mCi. Rest imaging isperformed beginning at between about 1.5 and about 3 minutes afterinjection, such as between about 1.75 and about 2.25 minutes (e.g., atabout 2 minutes) after injection. The duration of the imaging istypically between about 2 and about 4 minutes, e.g., about 3 minutes.

As with the other protocols described herein, this protocol is typicallyimplemented using an automated administration system, such as automatedadministration system 56, described hereinabove with reference to FIG.4.

Alternatively, one of the following techniques is used for performingthe stress and rest imaging, after the rest injection of teboroxime andthe stress injection of thallium have been performed:

-   -   According to a first technique, first rest imaging of the        teboroxime is performed, typically having a duration of between        about 2 and about 4 minutes, e.g., about 3 minutes. Upon        completion of the teboroxime rest imaging, at which point the        teboroxime has substantially cleared from the heart, but the        thallium has not yet substantially cleared from the heart,        stress imaging of the thallium is performed. Because of the        different energy levels of the teboroxime and the thallium,        emissions from the thallium during the imaging of the teboroxime        do not generally substantially interfere with the teboroxime        imaging. For some applications, the rest and stress imaging are        performed during a single scanning session, while for other        applications, there is a delay between the completion of the        rest imaging and the commencement of the stress imaging.    -   According to a second technique, rest imaging of the teboroxime        and stress imaging of the thallium are performed simultaneously,        utilizing the different energy levels of the two        radiopharmaceuticals.

Application of stress, whether physical or pharmacological, generallycauses the patient to move (exercise clearly involves motion, andpharmacological stress is often uncomfortable for the patient).Application of the stress before the imaging portion of the protocolbegins allows the performance of the stress and the rest imaging withoutan intervening application of stress. As a result, there is a highlikelihood that the patient will remain in the same position for boththe stress and rest imaging, which enables the registration of theresulting stress and rest images with one another. The patient'sremaining in the same position between the two scans also obviates theneed to separately set imaging parameters (such as physicallocation/orientation of the imaging elements of the camera) for the twoscans. In an embodiment of the present invention, imaging parameters areset just once for two or more imaging acquisitions, such as for a stressimaging acquisition and a rest imaging acquisition.

FIG. 6C is a timeline illustrating an ultra-fast teboroximerest/thallium pharmacological stress protocol, in accordance with anembodiment of the present invention. This protocol is similar to theprotocol described hereinabove with reference to FIG. 6A, except thatthe stress portion of the protocol is performed with thallium ratherthan teboroxime. Typically, the stress thallium has a dose of betweenabout 3 and about 5 mCi, and the stress imaging has a duration ofbetween about 3 and about 5 minutes, e.g., about 4 minutes.

This protocol enables the quick performance of a myocardial perfusionstudy (in about 15 minutes), which is convenient for the patient, andallows high throughput for the imaging facility. This protocol takesadvantage of the narrow window of opportunity provided by the teboroximeuptake curve, i.e., after lung clearance at about 2 minutes afterinjection, and prior to substantial liver uptake beginning at about 5minutes after injection. As mentioned above, this protocol is typicallyimplemented using an automated administration system, such as automatedadministration system 56, described hereinabove with reference to FIG.4. Such automated administration is typically performed while thepatient is positioned at the imaging system. Such automation isconvenient for the technician, the physician, and the patient, becausethe entire procedure is completed in about 15 minutes without thepatient having to leave the imaging system. Such automation alsosubstantially reduces the likelihood of error in administration.

In an alternative embodiment of this protocol, the teboroxime injectionis performed under stress, followed by stress imaging of the teboroxime,and, thereafter, the thallium injection is performed at rest, followedby rest imaging of the thallium. As mentioned above, the application ofthe stress before both image acquisitions, rather than between the imageacquisitions, increases the likelihood that registration of the stressand rest images can be performed.

FIG. 6D is a timeline illustrating a vasodilator-enhanced ultra-fastteboroxime rest/thallium pharmacological stress protocol for a viabilitystudy, in accordance with an embodiment of the present invention. Theprotocol begins with the injection of teboroxime while the patient is atrest. The dose of this first injection is typically between about 6 andabout 15 mCi, such as about 8 and about 12 mCi, e.g., between about 9and about 11 mCi. Rest imaging is performed beginning at between about1.5 and about 3 minutes after injection, such as between about 1.75 andabout 2.25 minutes (e.g., at about 2 minutes) after injection. Theduration of the imaging is typically between about 2 and about 4minutes, e.g., about 3 minutes. A vasodilator, such as nitroglycerin(e.g., sublingual, as a tablet or spray) or isosorbide dinitrate isadministered at about 1 to about 3 minutes after the completion of therest imaging, e.g., at about 2 minutes after the completion of the restimaging, and/or at about 6 to about 8 minutes after the initialteboroxime injection, e.g., at about 7 minutes. For applications inwhich the vasodilator comprises nitroglycerin, the nitroglycerintypically has a dose of between about 0.3 mg and about 0.6 mg ifadministered sublingually, and about 1 mg if administered buccally. Forapplications in which the vasodilator comprises isosorbide dinitrate,the isosorbide dinitrate typically has a dose of about 5 mg for chewableadministration, and between about 2.5 mg and about 5 mg for sublingualadministration. An injection of teboroxime is performed, typicallybetween about 2 and about 3 minutes after administration of thevasodilator. This injection typically has a dose of between about 20 andabout 40 mCi, e.g., between about 25 and about 35 mCi. Viability imagingis performed, typically beginning upon completion of the secondteboroxime injection (e.g., at about 9 minutes from the first teboroximeinjection if the second teboroxime injection is performed 2 minutesafter administration of the vasodilator) or soon thereafter, andtypically with a duration of between about 3 and about 5 minutes, e.g.,about 4 minutes.

This protocol enables the quick performance of a myocardial perfusionstudy (in about 15 minutes), which is convenient for the patient, andallows high throughput for the imaging facility. This protocol takesadvantage of the narrow window of opportunity provided by the teboroximeuptake curve, i.e., after lung clearance at about 2 minutes afterinjection, and prior to substantial liver uptake beginning at about 5minutes after injection. As mentioned above, this protocol is typicallyimplemented using an automated administration system, such as automatedadministration system 56, described hereinabove with reference to FIG.4. Such automated administration is typically performed while thepatient is positioned at the imaging system. Such automation isconvenient for the technician, the physician, and the patient, becausethe entire procedure is completed in about 15 minutes without thepatient having to leave the imaging system. Such automation alsosubstantially reduces the likelihood of error in administration.

Nitroglycerin is believed to exert its primary vasodilatory effect onepicardial conductance vessels. Thus, nitroglycerin appears topreferentially direct blood flow to post-stenotic zones of ischemia.This leads to increased uptake of the stress radiopharmaceutical inregions where the ischemic tissue is still viable. Patients with viabletissue are more likely to respond well to revascularization thanpatients with irreversibly damaged tissue.

For some applications, the vasodilator is administered together withpharmacological stress, such an adenosine or persantine infusion. Theinfusion typically has a lower dose than is used for pharmacologicalstress alone. For example, the lower dose may be between about 60μg/kq/min and about 80 μg/kq/min, e.g., about 70 μg/kq/min.

For some applications, the stress portion of this protocol is performedusing thallium rather than teboroxime. Typically, the stress thalliumhas a dose of between about 3 and about 5 mCi, and the stress imaginghas a duration of between about 3 and about 5 minutes, e.g., about 4minutes.

FIG. 6E is a timeline illustrating a low-dose teboroxime rest/teboroximepharmacological stress protocol, in accordance with an embodiment of thepresent invention. The protocol begins with the injection of teboroximewhile the patient is at rest. The dose of this first injection istypically less than 5 mCi, such as less than or equal to 4.5 mCi, lessthan or equal to 4 mCi, or less than or equal to 3 mCi, e.g., betweenabout 2 and about 3 mCi. Rest imaging is performed beginning at betweenabout 1.5 and about 3 minutes after injection, such as between about1.75 and about 2.25 minutes (e.g., at about 2 minutes) after injection.The duration of the imaging is typically between about 2 and about 12minutes, such as between about 4 and about 10 minutes, e.g., betweenabout 6 and about 8 minutes.

Pharmacological stress is applied, such as by infusion of adenosine orpersantine, beginning at about 1 to about 3 minutes after the completionof the rest imaging, e.g., at about 2 minutes after the completion ofthe rest imaging, and/or about 14 minutes after the initial teboroximeinjection. The infusion typically has a duration of between about 3 andabout 5 minutes, e.g., about 4 minutes. A stress injection of teboroximeis performed, typically between about 1 and about 3 minutes aftercommencement of the infusion, e.g., about 2 minutes after commencement.The stress injection typically has a dose of between about 12 and about18 mCi. Stress imaging is performed, typically upon completion of thestress infusion (e.g., at about 18 minutes from the first teboroximeinjection) or soon thereafter, and typically with a duration of betweenabout 15 and about 25 minutes, e.g., about 20 minutes.

This protocol enables the use of lower doses of teboroxime than werepossible or contemplated in the past to the knowledge of the inventors.The use of such lower doses increases safety for both the patient andthe technician. This protocol also decreases the contamination of theliver, with a consequent improvement in image quality. In addition, thisprotocol enables quick performance of a myocardial perfusion study (inabout 40 minutes), which is convenient for the patient, and allows highthroughput for the imaging facility. This protocol takes advantage ofthe narrow window of opportunity provided by the teboroxime uptakecurve, i.e., after lung clearance at about 2 minutes after injection,and prior to substantial liver uptake beginning at about 5 minutes afterinjection. As mentioned above, this protocol is typically implementedusing an automated administration system, such as automatedadministration system 56, described hereinabove with reference to FIG.4. Such automated administration is typically performed while thepatient is positioned at the imaging system. Such automation isconvenient for the technician, the physician, and the patient, becausethe entire procedure is completed in about 15 minutes without thepatient having to leave the imaging system. Such automation alsosubstantially reduces the likelihood of error in administration.

FIG. 6F is a timeline illustrating a teboroxime pharmacologicalstress-only protocol, in accordance with an embodiment of the presentinvention. The protocol begins with the application of pharmacologicalstress, such as by infusion of adenosine or persantine. The infusiontypically has a duration of between about 3 and about 5 minutes, e.g.,about 4 minutes. A stress injection of teboroxime is performed,typically between about 1 and about 3 minutes after commencement of theinfusion, e.g., about 2 minutes after commencement. The stress injectiontypically has a dose of between about 6 and about 12 mCi, e.g., about 8and about 10 mCi. Stress imaging is performed, typically beginningsubstantially simultaneously with the injection, and continuing untilthe conclusion of the protocol, typically at about 6 to about 10minutes, e.g., about 8 minutes from the commencement of the infusion.One or more additional stress teboroxime injections are performed duringthe imaging, such as at about 1 minute and about 2 minutes after thefirst teboroxime injection. Typically, the one or more additionalinjection are spaced apart by at least 30 seconds, such as by betweenabout 45 and about 90 seconds, e.g., by about 60 seconds. Theseadditional one or more injections typically have about the same dose asthe first injection. Alternatively, all or a portion of the one or moreinjections has a different respective dose.

The early stress and serial images provided by this protocol, whichinclude rest, stress, and washout images, provide the physician withadditional valuable kinetic information that has not been available inthe past using conventional imaging techniques. In addition, asmentioned hereinabove, with reference to FIG. 2, the imaging istypically performed while the patient is substantially upright, andusing ROI-centric imaging. These techniques reduce the interference ofemissions from the liver. Such reduced interference, in combination withthe high-resolution, rapid imaging enabled by imaging system 10, enablethe performance of serial imaging after stress, in order to assesspost-stress left-ventricular function recovery (i.e., by identifyingstunning myocardium). Such serial imaging can be characterized asdynamic imaging with 2-minute frames. A study performed with thisprotocol, while not providing absolute flow measurements, does provideflow estimates, which for some applications obviate the need to performa rest study. In summary, the sequential injection of teboroxime enablesthe monitoring of changes in uptake and washout dynamics as a functionof post-stress recovery.

Furthermore, this protocol enables the quick performance of a myocardialperfusion study (in less than about 10 minutes), which is convenient forthe patient, and allows high throughput for the imaging facility. Thisprotocol takes advantage of the narrow window of opportunity provided bythe teboroxime uptake curve, i.e., after lung clearance at about 2minutes after injection, and prior to substantial liver uptake beginningat about 5 minutes after injection. As mentioned above, this protocol istypically implemented using an automated administration system, such asautomated administration system 56, described hereinabove with referenceto FIG. 4. Such automated administration is typically performed whilethe patient is positioned at the imaging system. Such automation isconvenient for the technician, the physician, and the patient, becausethe entire procedure is completed in no more than about 15 minuteswithout the patient having to leave the imaging system. Such automationalso substantially reduces the likelihood of error in administration.

FIG. 6G is a timeline illustrating a teboroxime pharmacologicalstress-only protocol, in accordance with an embodiment of the presentinvention. This protocol is similar to the protocol describedhereinabove with reference to FIG. 6F, except that only a single stressinjection of teboroxime is performed, typically with a dose of betweenabout 20 and about 40 mCi, e.g., between about 25 and about 35 mCi.

This protocol enables the quick performance of a myocardial perfusionstudy (in less than about 10 minutes), which is convenient for thepatient, and allows high throughput for the imaging facility. Thisprotocol takes advantage of the narrow window of opportunity provided bythe teboroxime uptake curve, i.e., after lung clearance at about 2minutes after injection, and prior to substantial liver uptake beginningat about 5 minutes after injection. As mentioned above, this protocol istypically implemented using an automated administration system, such asautomated administration system 56, described hereinabove with referenceto FIG. 4. Such automated administration is typically performed whilethe patient is positioned at the imaging system. Such automation isconvenient for the technician, the physician, and the patient, becausethe entire procedure is completed in no more than about 15 minuteswithout the patient having to leave the imaging system. Such automationalso substantially reduces the likelihood of error in administration.

FIG. 6H is a timeline illustrating a dual-isotope teboroximestress/I-123 BMIPP protocol, for a combined perfusion and fatty acidimaging study, in accordance with an embodiment of the presentinvention. I-123 BMIPP is a fatty acid imaging agent that has beenavailable in Japan for many years, and is currently in Phase In clinicaltrials in the United States. BMIPP is characterized by “ischemicmemory,” in which an area at risk of acute myocardial infarction canstill be detected as a defect even a couple of weeks after successfulreperfusion therapy. For myocardial viability studies, image analysis isbased on comparison between BMIPP and a perfusion tracer.

As reported by the above-mentioned article by Dilsizian V et al., inacute myocardial infarctions, a strong association has been reported, onthe one hand, between a “negative” mismatch (i.e., BMIPP less thanperfusion) and jeopardized but viable myocardium, and, on the otherhand, between a matched decreased uptake of both tracers and nonviabletissue. In chronic infarctions, the number of segments with less BMIPPthan perfusion has been shown to be the strongest predictor of adversecardiac events at follow-up. A “positive” mismatch with more BMIPP thanperfusion, although rarely encountered, appears to be associated withunstable conditions or severe wall motion abnormalities. In sum, thecombined evaluation of BMIPP and perfusion reliably differentiatesbetween viable and nonviable myocardial tissue in both acute and chronicphases of ischemic heart disease. It is also a useful tool for viabilityassessment with SPECT. A negative mismatch with less BMIPP thanperfusion identifies viable tissue, whereas a matched decreased uptakeof both tracers corresponds to myocardial scar.

The protocol begins with the injection of teboroxime while the patientis at rest. The dose of this first injection is typically between about6 and about 15 mCi, such as between about 8 and about 12 mCi, e.g.,between about 9 and about 11 mCi. Rest imaging is performed beginning atbetween about 1.5 and about 3 minutes after injection, such as betweenabout 1.75 and about 2.25 minutes (e.g., at about 2 minutes) afterinjection. The duration of the imaging is typically between about 2 andabout 4 minutes, e.g., about 3 minutes.

Pharmacological stress is applied, such as by infusion of adenosine orpersantine, beginning at about 0.5 to about 3 minutes after thecompletion of the rest imaging, e.g., at about 1 minute after thecompletion of the rest imaging, and/or at about 5 to about 7 minutesafter the initial teboroxime injection, e.g., at about 6 minutes. Theinfusion typically has a duration of between about 3 and about 5minutes, e.g., about 4 minutes. A stress injection of I-123 BMIPP isperformed, typically between about 1 and about 3 minutes aftercommencement of the stress, e.g., about 2 minutes after commencement.The stress injection typically has a dose of between about 3 and about 5mCi. Stress imaging is performed, typically upon completion of thestress infusion (e.g., at about 10 minutes from the teboroximeinjection) or soon thereafter, and typically with a duration of betweenabout 4 and about 6 minutes, e.g., about 5 minutes.

For some applications, imaging system 10 performs the imaging of theBMIPP uptake using static imaging, in which the resulting image iscompared with the teboroxime perfusion study. Alternatively, the imagingsystem performs the imaging of the BMIPP uptake using dynamicacquisition, in order to calculate flow measurements and performquantitative assessment of the I-123 BMIPP total myocardial uptake ratio(TMUR).

FIG. 6I is a timeline illustrating a dual-isotope simultaneous-imagingteboroxime rest/I-123 BMIPP protocol, for a combined perfusion and fattyacid imaging study, in accordance with an embodiment of the presentinvention. This protocol is generally appropriate for use in anemergency room setting, when a patient has suffered an acute eventand/or presents with chest pain of unknown cause. Under suchcircumstances, the performance of stress imaging is generally notrecommended.

The protocol begins with the simultaneous or near-simultaneous injectionof teboroxime and BMIPP while the patient is at rest. Typically, theteboroxime and the BMIPP are administered as a mixture (i.e., acocktail); alternatively, the teboroxime and the BMIPP are administeredseparately. The dose of the teboroxime is typically between about 6 andabout 15 mCi, such as about 8 and about 12 mCi, e.g., between about 9and about 11 mCi, and the dose of the BMIPP is typically between about 3and about 5 mCi. Simultaneous rest imaging of both radiopharmaceuticalsis performed beginning at between about 1.5 and about 3 minutes afterinjection, such as between about 1.75 and about 2.25 minutes (e.g., atabout 2 minutes) after injection. The duration of the imaging istypically between about 2 and about 4 minutes, e.g., about 3 minutes.The imaging system produces separate images of each radiopharmaceuticalagent by separating the energies of the two isotopes, while imaging bothisotopes simultaneously. The result is two separate images, each ofwhich provides the uptake a respective one of the tracers.

This dual-isotope protocol enables the identification of some ischemicevents that could not otherwise be identified in a myocardialperfusion-only study. For example, if a patient suffers a minormyocardial event, by the time the patient reaches the hospital perfusionmay be restored to the infarcted area. In such a case, a myocardialperfusion-only study would not be capable of detecting the event.Because of the ischemic memory characteristic of BMIPP, the presentdual-isotope protocol is likely to identify the ischemic event.Furthermore, the protocol is quick (about 5 minutes total time), whichis suitable for emergency room settings.

FIG. 6J is a timeline illustrating a dual-isotope teboroxime rest/Tc-99mECDG stress protocol for a combined perfusion and static glucosemetabolism imaging study, in accordance with an embodiment of thepresent invention. The protocol begins with the injection of teboroximewhile the patient is at rest. The dose of this first injection istypically between about 6 and about 15 mCi, such as about 8 and about 12mCi, e.g., between about 9 and about 11 mCi. Rest imaging is performedbeginning at between about 1.5 and about 3 minutes after injection, suchas between about 1.75 and about 2.25 minutes (e.g., at about 2 minutes)after injection. The duration of the imaging is typically between about2 and about 4 minutes, e.g., about 3 minutes.

Pharmacological stress is applied, such as by infusion of adenosine orpersantine, beginning at about 0.5 to about 3 minutes after thecompletion of the rest imaging, e.g., at about 1 minute after thecompletion of the rest imaging. The infusion typically has a duration ofbetween about 3 and about 5 minutes, e.g., about 4 minutes. A stressinjection of Tc-99m ECDG is performed, typically between about 1 andabout 3 minutes after commencement of the infusion, e.g., about 2minutes after commencement. The ECDG typically has a dose of betweenabout 20 and about 40 mCi, e.g., between about 25 and about 35 mCi.During ischemia, ischemic cells begin to metabolize glucose instead offatty acids, resulting in an increased uptake of ECDG. Static stressimaging is performed upon completion of the pharmacological stress orsoon thereafter, typically with a duration of between about 3 and about5 minutes, e.g., about 4 minutes.

This protocol enables the quick performance of a combined myocardialperfusion and static glucose metabolism study (in about 15 minutes),which is convenient for the patient, and allows high throughput for theimaging facility. This protocol takes advantage of the narrow window ofopportunity provided by the teboroxime uptake curve, i.e., after lungclearance at about 2 minutes after injection, and prior to substantialliver uptake beginning at about 5 minutes after injection. As mentionedabove, this protocol is typically implemented using an automatedadministration system, such as automated administration system 56,described hereinabove with reference to FIG. 4. Such automatedadministration is typically performed while the patient is positioned atthe imaging system. Such automation is convenient for the technician,the physician, and the patient, because the entire procedure iscompleted in about 15 minutes without the patient having to leave theimaging system. Such automation also substantially reduces thelikelihood of error in administration.

FIG. 6K is a timeline illustrating a dual-isotope teboroxime rest/Tc-99mECDG stress protocol, for a combined perfusion and dynamic glucosemetabolism imaging study, in accordance with an embodiment of thepresent invention. This protocol is similar to the protocol describedhereinabove with reference to FIG. 6J, except that the stress imaging isperformed using dynamic acquisition, typically with frames having aduration of between about 20 seconds to about 1 minute. A longer stressimaging duration is consequently used, such as between about 4 and about6 minutes, e.g., about 5 minutes.

This protocol enables the quick performance of a combined myocardialperfusion and dynamic glucose metabolism study (in about 15 minutes),which is convenient for the patient, and allows high throughput for theimaging facility. This protocol takes advantage of the narrow window ofopportunity provided by the teboroxime uptake curve, i.e., after lungclearance at about 2 minutes after injection, and prior to substantialliver uptake beginning at about 5 minutes after injection. As mentionedabove, this protocol is typically implemented using an automatedadministration system, such as automated administration system 56,described hereinabove with reference to FIG. 4. Such automatedadministration is typically performed while the patient is positioned atthe imaging system. Such automation is convenient for the technician,the physician, and the patient, because the entire procedure iscompleted in about 15 minutes without the patient having to leave theimaging system. Such automation also substantially reduces thelikelihood of error in administration.

FIG. 6L is a timeline illustrating a dynamic study for performing bloodflow measurements and calculation of coronary flow reserve (CFR), inaccordance with an embodiment of the present invention. The protocolbegins with the injection of teboroxime while the patient is at rest,followed by flushing in order to prevent contamination of the subsequentinjection (described below). The dose of this first injection istypically between about 6 and about 15 mCi, such as between about 8 andabout 12 mCi, e.g., between about 9 and about 11 mCi. The flush istypically performed with between about 8 and about 12 ml of salinesolution, e.g., about 10 ml of saline solution. Beginning substantiallysimultaneously with the injection (or even slightly prior thereto), suchas less than 10 seconds after completion of the injection, e.g., lessthan 5 seconds or less than 2 seconds, low-resolution rest imaging isperformed, typically for between about 20 and about 40 seconds, e.g.,about 30 seconds. (It is noted that the scope of the phrase “beginningless than a certain number of seconds after completion of the injection”or similar phrases, as used herein, including in the claims, is intendedto include beginning even prior to completion of the injection, and evenprior to commencement of the injection.) Each of the frames typicallyhas a short duration of between about 3 and about 7 seconds, e.g., about5 seconds. The low-resolution rest imaging is used to estimate the inputfunction, which will is used later in the protocol in combination thehigh-resolution imaging to calculate absolute flow measurements, asdescribe hereinbelow.

High-resolution imaging is performed with longer frames, beginningsubstantially immediately upon completion of the low-resolution restimaging, e.g., less than 10 seconds after completion, such as less than5 seconds or less than 2 seconds. These frames typically have a durationof between about 15 to about 25 about seconds, e.g., about 20 seconds,which frame duration is typically at least 2 times greater than theduration of the low-resolution frames, e.g., at least 3 or 5 timesgreater. The high-resolution imaging typically has a total duration ofbetween about 4 and about 6 minutes, e.g., about 4.5 minutes.

Pharmacological stress is applied, such as by infusion of adenosine orpersantine, typically beginning substantially upon completion of thehigh-resolution rest imaging, or within about an hour after completionof the high-resolution rest imaging. The infusion typically has aduration of between about 3 and about 5 minutes, e.g., about 4 minutes.Typically, between about 1 and about 3 minutes after commencement of thestress, e.g., about 2 minutes after commencement, a stress injection ofteboroxime is performed, typically having a dose of between about 20 andabout 40 mCi, e.g., between about 25 and about 35 mCi. Typicallysubstantially immediately upon completion of the stress infusion (e.g.,at about 7 minutes from the first, rest teboroxime injection) or soonthereafter, e.g., within 10 seconds of completion of the stressinfusion, low-resolution stress imaging is performed, typically forbetween about 20 and about 40 seconds, e.g., about 30 seconds. Each ofthe frames typically has a short duration of between about 3 and about 7seconds, e.g., about 5 seconds. The low-resolution stress imaging isused to estimate counts in the blood pool (i.e., the left and rightventricular chambers), from which the input function is derived, asdescribed hereinbelow.

High-resolution stress imaging is performed with longer frames,beginning substantially immediately upon completion of thelow-resolution stress imaging. These frames typically have a duration ofbetween about 15 and about 25 seconds, e.g., about 20 seconds. Thehigh-resolution imaging typically has a total duration of between about4 and about 6 minutes, e.g., about 4.5 minutes:

This protocol enables the assessment of absolute myocardial perfusionand CFR. By sampling the myocardium in approximately 5-second intervalsduring the first, low-resolution phase, the system accurately estimatesthe input function. As described above, once the tracer begins todiffuse into the myocardium, the sampling time of the myocardium istypically increased to approximately 30-second intervals. The systemanalyzes these dynamic sequences using a compartmental analysisapproach. This protocol generally requires precise knowledge of the rateof the injection of the bolus, and a flush immediately following theinjection of the radiopharmaceutical. For this reason, the injection istypically performed using an automated administration system, such asautomated administration system 56, described hereinabove with referenceto FIG. 4. In addition, it is generally important that the bolus have arelatively small volume. For this reason, the teboroxime and the salineflush (and, typically, the stress pharmacological agent) are typicallysupplied in a pre-packaged ready-to-use radiopharmaceutical agentcontainer 54 that is loaded into the automated administration system, asdescribed hereinabove with reference to FIG. 4. The flush is used topush the bolus through and to complete the injection over a short periodof time, as well as to wash out residual radioactivity from the infusionline, so that this activity does not contaminate the next bolusinjection. The entire rest-stress procedure is typically performed inless than about 15 minutes, and provides absolute blood flowmeasurements for both rest and stress studies.

This protocol generally enables the achievement of better contrast incoronary flow reserve for those patients with distributed coronarydisease at an earlier stage in the development of the disease, than ispossible using conventional imaging techniques.

In respective embodiments of the present invention, theradiopharmaceuticals used in any of the protocols described herein areprovided in a kit, and/or in a container. For protocols including morethan one radiopharmaceutical, the radiopharmaceuticals may be storedmixed together in a single compartment of the container, such as if theprotocol calls for simultaneous administration of theradiopharmaceuticals, or separately in separate compartments of thecontainer, such as if the protocol calls for separate administration ofthe radiopharmaceuticals. Typically, the container contains information;such as protocol, patient information, administration, cameraconfiguration information (e.g., scanning parameters), or analysisinformation, or is associated with a data carrier containing suchinformation. For example, techniques may be used that are described inU.S. patent application Ser. No. 11/750,057, filed May 17, 2007, and/orin International Patent Application PCT/IL2006/000562, filed May 11,2006, which published as PCT Publication WO 06/129301. Furthermore, theprotocols described herein are typically implemented using an automatedadministration system, such as automated administration system 56,described hereinabove with reference to FIG. 4. Such automatedadministration is typically performed while the patient is positioned atthe imaging system. Alternatively, these protocols are performed usingmanual administration, or a combination of automated and manualadministration. These protocols are typically used to producequantitative results, such as quantitative measures of flow of perfusionagents, and/or the percentage of the myocardium that is ischemic for ametabolic agent.

For some applications, this protocol is performed in combination withtechniques described in the above-cited article by El Fakhri G et al.,mutatis mutandis.

For some applications, the protocols described hereinabove withreference to FIG. 6A-H or 6J-L are performed using exercise stressinstead of pharmacological stress. Typically, the stress injectionoccurs once a determination is made that the patient has achieved athreshold percentage of cardiac output, such as at least 85% or at least100%, as is known in the art. Such cardiac output typically occursbetween about 1 and about 3 minutes after commencement of exercise, suchas about 2 minutes after commencement of exercise. The exercisetypically continues for a total of between about 5 minutes and about 15minutes, e.g., about 10 minutes.

For some applications, the protocols described herein that include theapplication of pharmacological stress are performed using a bolusinjection of A2A, rather than an infusion of adenosine or persantine.

In an embodiment of the present invention, a protocol is provided thatcomprises pre-administrating a trace quantity of a radiopharmaceutical,and performing a scan of the patient to determine a location of thepatient's heart based on the radiation emitted from theradiopharmaceutical. A trace quantity is typically a quantity that lessthan about 2 mCi, less than 1 mCi, less than 0.5, or less 0.1 mCi.Alternatively, the trace quantity is less than 10% of the quantity usedfor the diagnostic imaging. The camera (e.g., the position and/ororientation of the camera) of the imaging system is configured, based onthe determined location of the heart. Teboroxime is administered to thepatient at a dose appropriate for imaging, such as one the dosesdescribed herein, and an imaging procedure is performed. For someapplications, the trace radiopharmaceutical comprises thallium-chlorideor Tc-99m, such as ^(99m)Tc-sestamibi, ^(99m)Tc-tetrofosmin, orteboroxime. For some applications, the trace radiopharmaceutical and theimaging-dose teboroxime are supplied in a kit configured to be used withan automated administration system, such as described herein.

In an embodiment of the present invention, teboroxime is administered inconjunction with image acquisition by the camera. Typically, the imagebegins prior to the administration, or at the time of administration, orwithin three minutes after administration. Photons are acquired in listmode, and the kinetics of the teboroxime in the myocardium are analyzedto produce a quantification of coronary flow reserve (CFR). Typically,the protocol comprises acquiring the image only during rest or onlyduring stress (such as physical or pharmacological stress, e.g., byinfusion of adenosine or persantine). For some applications, theteboroxime and the stress agent are supplied in a kit configured to beused with an automated administration system. The information regardingthe time of administration may be provided to or from the camera.

In respective embodiments of the present invention, the protocolsdescribed herein, including hereinabove with reference to FIGS. 6A-L,further comprise performance of washout imaging, typically beginningupon completion of the stress imaging, or soon thereafter. Washoutimaging is performed to investigate the washout kinetics of theparticular tracer. Since washout kinetics in healthy myocardium maydiffer from the washout kinetics of ischemic or infarcted tissue, thistype of analysis may provide clinically meaningful information for amore accurate diagnosis. Significant washout of teboroxime occurs twominutes after injection (at the time of peak uptake) and continues forabout 10 minutes after injection. This type of analysis may be performedas an extension of any one of the protocols mentioned herein. For someapplications, such washout imaging is performed as a semi-quantitativemeasurement of flow by comparing sequential two-minute images. Forabsolute flow measurements, the dynamic protocols (e.g., 10 secondscans) are typically extended for up to 10 minutes to analyze thewashout kinetics with absolute flow rates in different regions of themyocardium. For some applications, such washout imaging is performed todetermine a non-dynamic estimate of tracer intensity. For someapplications, the result may be a display of an “image” of the kineticparameters (k1, k2, . . . ) per location in 3D space (or a list of suchvalues of the kinetic parameters for selected regions, without full 3Dpresentation), such as described, for example, in above-mentionedInternational Application PCT/IL2006/001291 (see the section entitled“Kinetic Modeling”).

In respective embodiments of the present invention, gating is performedon the stress acquisitions of protocols described herein, includingthose described hereinabove with reference to FIGS. 6A-L, for exampleusing 8, 16, or 32 bins. For performing this gating, techniques may beused that are described in one or more of the references incorporatedherein by reference, including the patent and patent applicationpublications.

The higher resolution provided by the techniques described hereincompared to conventional SPECT imaging techniques generally reducespartial volume effects, which are caused by a portion of the imagedvoxels falling partially within both blood and cardiac tissue. Thesepartial volume effects are particularly detrimental to dynamic imagingstudies, which rely on quantitative analysis of curves over time. Suchslope analysis necessarily increases noise, which is further aggravatedby the presence of partial voxels as input. For some applications, inorder to further reduce partial volume effects, the imaging system usesa non-uniform voxel grid, such as by using sub-voxels and/or adaptivevoxel borders. For example, techniques described in above-mentionedInternational Application PCT/IL2006/001291 may be used for thispurpose.

In accordance with respective embodiments of the present invention,dual-radiopharmaceutical protocols include the administration andsimultaneous imaging of the following combinations of teboroxime withone or more other labeled radiopharmaceutical agents and/orpharmacological stress agents. Typically, the teboroxime and theagent(s) are administered as a mixture (i.e., a cocktail) before orduring a simultaneous imaging procedure; alternatively, the teboroximeand/or the agent(s) are administered separately before or during asimultaneous imaging procedure.

-   -   (a) teboroxime, and (b) I-123 BMIPP, for simultaneously studying        myocardial perfusion and fatty acid metabolism;    -   (a) teboroxime, and (b) Tc-99m ECDG, for simultaneously studying        myocardial perfusion and glucose metabolism (during ischemia,        ischemic cells begin to metabolize glucose instead of fatty        acids, resulting in an increased uptake of ECDG);    -   (a) teboroxime, and (b) Tl-201-thallous chloride, for a dynamic        myocardial perfusion study that analyzes the different kinetics        of the teboroxime and the thallium, for either a rest or stress        study. The teboroxime typically has a low dose, such that        Compton residuals produced by the teboroxime do not mask the        emissions of the thallium, such as described with reference to        FIG. 18 of the above-reference International Application        PCT/IL2006/000562. For some applications, the protocol includes        an initial low-resolution portion having relatively short        frames, followed by a higher-resolution portion having longer        frames, such as described hereinabove with reference to FIG. 6L,        for example, in order to provide quantitative kinetic        information for both tracers; and    -   (a) teboroxime, and (b) ¹²³I-Fatty acid, for simultaneously        studying myocardial perfusion and fatty acid metabolism.

In an embodiment of the present invention, a multiple isotopecombination protocol is provided for studying different pathologicalprocesses indicative of acute myocardial ischemia. In accordance withthis protocol, the following labeled radiopharmaceutical agents areadministered as bolus IV injections:

-   -   (a) I-123-BMIPP, at a dose of between about 0.5 and about 2.5        mCi, e.g., about 2 mCi, followed by a wait of about 30 to about        60 minutes;    -   (b) Tl-201-thallous chloride, at a dose of between about 0.5 to        about 2 mCi, e.g., about 1 mCi; and    -   (c) teboroxime, at a dose of between about 8 and about 12 mCi,        e.g., about 10 mCi.

Agents (b) and (c) are administered as a cocktail, or as separateinjections at approximately the same time (in which case the thallium istypically administered first). Simultaneous image acquisition of allthree radiopharmaceutical agents is performed during or soon afteradministration of agents (b) and (c), typically using an up to about 30minute acquisition time, such as between about 5 and about 15 minutes,which is faster than that of standard imaging protocols. Typically,camera 22 of imaging system 10 performs image acquisition using anenergy window of between about 2% and about 10% of the emitted energylevels of the radiopharmaceutical agents. Typically, detectors 40 ofcamera 22 sweep the region of interest once every approximately 10 toapproximately 15 seconds. Simultaneous imaging provides more accurateidentification of myocardial perfusion pathologies than is generallypossible using conventional imaging techniques and protocols.

In an embodiment of the present invention, a fast, single-isotope,combined rest and stress teboroxime imaging protocol is provided. Whileunder the camera, a patient is injected with about 8-10 mCi teboroxime,and rest imaging is performed with a duration of about 2 to about 5minutes, e.g., about 3 minutes. The patient is then subject topharmacological stress, for example, by the administration of adenosineor persantine. At the peak stress level, the patient is injected withabout 20-30 mCi teboroxime, while under the camera. Substantiallyimmediately after the second injection, a post-stress imaging isperformed with a duration of between about 1 and about 4 minutes, e.g.,about 2 minutes. The total imaging time of this protocol is betweenabout 3 and about 7 minutes, e.g., about 5 minutes.

In an embodiment of the present invention, a rest teboroxime cardiacperfusion protocol is provided. The perfusion is described byquantitative parameters (ml/min/gr), coronary flow reserve, andparametric quantitation. While under the camera, a patient is injectedwith up to about 30 mCi teboroxime, and imaging is begun immediately.Imaging is performed for up to about 15 minutes, with an energy windowof between about 3% and about 15%. This protocol enables the study offluid flow, rate of tracer uptake (passive or active), traceraccumulation and redistribution, tracer metabolism, and secretion and/orwashout (active or passive) of tracer/metabolites.

In an embodiment of the present invention, a stress teboroxime cardiacperfusion protocol is provided. The perfusion is described byquantitative parameters (ml/min/gr), coronary flow reserve, andparametric quantitation. A patient is subjected to pharmacologicalstress, for example, by the administration of adenosine or persantine,or to physical stress, for example, by exercising on a treadmill. At thepeak stress level, while under the camera, the patient is injected withup to about 4 mCi teboroxime, and imaging is begun immediately. Imagingis taken for a time of up to 15 minutes, with an energy window ofbetween 3 and 15%. This protocol enables the study of fluid flow, rateof tracer uptake (passive or active), tracer accumulation andredistribution, tracer metabolism, and secretion and/or washout (activeor passive) of tracer/metabolites.

In an embodiment of the present invention, a fast, single-isotopeTc-99m-teboroxime imaging protocol is provided. While at rest, a patientis injected with about 8-10 mCi of teboroxime, typically while thepatient is under the camera, and a rest imaging procedure having aduration of about 10 minutes is performed. The patient is then subjectto a stress, such as pharmacological stress, e.g., by the administrationof adenosine or persantine. At peak stress level, the patient isinjected with about 20-30 mCi of teboroxime, typically while positionedunder the camera. Substantially immediately after the second injection,a post-stress imaging of about 2 minutes is taken. The total imagingtime of this protocol is about 12 minutes, and the total patient time isabout 20 minutes.

In an embodiment of the present invention, a protocol for studyingmyocardial perfusion and apoptosis is provided. A patient is injectedwith up to about 15 mCi teboroxime and up to about 1 to about 3 mCiIn-111-annexin, e.g., up to about 2 mCi In-111-annexin. After a waitingtime of up to about 24 hours, imaging is taken for a period of up toabout 30 minutes, with an energy window of between about 2% and about10%.

In respective embodiments of the present invention, all of the protocolsdescribed herein, including the protocols described hereinabove withreference to FIGS. 6A-L, are used to produce “clinically-valuableimages,” as defined hereinabove.

For some applications, the protocols described hereinabove, includingwith reference to FIGS. 6B and 6D, use another vasodilator instead ofnitroglycerin, such as isosorbide dinitrate. Similarly, protocolsdescribed herein as using adenosine for as a pharmacological stressagent may also use other stress agents, such as dipyridamole,persantine, or A2A.

Reference is made to FIG. 7, which is a graph showing hypothesizedteboroxime uptake over time in the liver and the vicinity of the liverin cases in which a tumor has uptake similar to vascularized tissue, inaccordance with an embodiment of the present invention. For such casesin which the tumor has uptake similar to vascularized tissue, which isquicker than that of healthy liver cells, the speed and sensitivity ofthe imaging techniques described herein enable the detection of theuptake and release of teboroxime from tumor cells in the liver prior tothe uptake and metabolism of the teboroxime by healthy liver cells.These techniques may be used to enable detection and diagnosis of tumorsof the liver. As can be seen in FIG. 7, the count of photons releasedfrom liver tumor cells during a time period T₁ is greater than the countof photons released from healthy liver cells, because tumor cells uptakethe teboroxime more rapidly than do healthy liver cells. Performingimaging during T₁ thus provides information regarding the uptake of theteboroxime by tumor cells, in a way which emphasizes the increaseduptake by the tumor cells compared to the uptake by the healthy livercells. For some applications, T₁ concludes at the point in time of theintersection of the uptake curves of the healthy liver cells and theliver tumor cells. For instance, in the example shown in FIG. 7, T₁concludes at about 110 seconds after administration of the teboroxime,while for other applications, T₁ concludes earlier, such as betweenabout 90 and about 110 seconds, e.g., at about 100 seconds.

FIG. 7 also shows the photon emission of background blood circulation.In general, to diagnose tumors not believed to be near blood vessels,the imaging procedure begins at about 0 seconds after administration,because the photon count spike of the blood circulation does not affectthe imaging. For applications in which the tumor is believed to be neara blood vessel, or the physician is otherwise concerned about the bloodpool of nearby blood vessels; the imaging procedure is performed duringthe time period T₂, which begins when the photon emissions of the bloodpool have dropped below the emissions of the tumor, i.e., at the pointin time of the intersection of uptake curves of the blood circulationand the liver tumor cells. For instance, in the example shown in FIG. 7,T₂ begins at between about 50 and about 60 seconds after administrationof the teboroxime.

In an embodiment of the present invention, these tumor diagnostictechniques are used to diagnosis tumors of other organs involved withmetabolic clearance, such as the gall bladder or the spleen.

In the protocols described herein, thallium is typically administered ata dose of between about 1 and 5 mCi, such as between 2 and 4 mCi.Alternatively, thallium is administered at a dose less than 1 mCi.

Although some protocols described herein are described as having amaximum dose of 40 mCi of Tc-99m (e.g., Tc-99m teboroxime), for someapplications these protocols use a higher dose, such as up to 50 mCi, 80mCi, or even 100 mCi. Although some protocols described herein aredescribed as having a dose of less than 5 mCi of Tc-99m (e.g., Tc-99mteboroxime), for some applications these protocols have a dose that isless than 2 mCi, or less than 1 mCi. Furthermore, the doses may varybased on physiological parameters of the subject, such as body mass.

The caret symbol (^) as used herein, including in the claims, signifiesan exponent.

The scope of the present invention includes embodiments described in thefollowing applications, which are assigned to the assignee of thepresent application and are incorporated herein by reference. In anembodiment, techniques and apparatus described in one or more of thefollowing applications are combined with techniques and apparatusdescribed herein:

-   -   International Patent Application PCT/IL2006/000562, filed May        11, 2006, entitled, “Unified management of radiopharmaceutical        dispensing, administration, and imaging,” which published as PCT        Publication WO 06/129301;    -   International Patent Application PCT/IL2005/001173, filed Nov.        9, 2005, which published as PCT Publication WO 06/051531;    -   International Patent Application PCT/IL2005/000572, filed Jun.        1, 2005, which published as PCT Publication WO 2005/118659;    -   International Patent Application PCT/IL2005/000575, filed Jun.        1, 2005, which published as PCT Publication WO 2005/119025;    -   International Patent Application PCT/IL2005/001215, filed Nov.        16, 2005, which published as PCT Publication WO 06/054296;    -   International Patent Application PCT/IL2006/001291, filed Nov.        9, 2006, which published as PCT Publication WO 2007/054935;    -   U.S. Provisional Patent Application 60/625,971, filed Nov. 9,        2004;    -   U.S. Provisional Patent Application 60/628,105, filed Nov. 17,        2004;    -   U.S. Provisional Patent Application 60/630,561, filed Nov. 26,        2004;    -   U.S. Provisional Patent Application 60/632,236, filed Dec. 2,        2004;    -   U.S. Provisional Patent Application 60/632,515, filed Dec. 3,        2004;    -   U.S. Provisional Patent Application 60/635,630, filed Dec. 14,        2004;    -   U.S. Provisional Patent Application 60/636,088, filed Dec. 16,        2004;    -   U.S. Provisional Patent Application 60/640,215, filed Jan. 3,        2005;    -   U.S. Provisional Patent Application 60/648,385, filed Feb. 1,        2005;    -   U.S. Provisional Patent Application 60/648,690, filed Feb. 2,        2005;    -   U.S. Provisional Patent Application 60/675,892, filed Apr. 29,        2005;    -   U.S. Provisional Patent Application 60/691,780, filed Jun. 20,        2005;    -   U.S. Provisional Patent Application 60/700,318, filed Jul. 19,        2005;    -   U.S. Provisional Patent Application 60/700,299, filed Jul. 19,        2005;    -   U.S. Provisional Patent Application 60/700,317, filed Jul. 19,        2005;    -   U.S. Provisional Patent Application 60/700,753, filed Jul. 20,        2005;    -   U.S. Provisional Patent Application 60/700,752, filed Jul. 20,        2005;    -   U.S. Provisional Patent Application 60/702,979, filed Jul. 28,        2005;    -   U.S. Provisional Patent Application 60/720,034, filed Sep. 26,        2005;    -   U.S. Provisional Patent Application 60/720,652, filed Sep. 27,        2005;    -   U.S. Provisional Patent Application 60/720,541, filed Sep. 27,        2005;    -   U.S. Provisional Patent Application 60/750,287, filed Dec. 13,        2005;    -   U.S. Provisional Patent Application 60/750,334, filed Dec. 15,        2005;    -   U.S. Provisional Patent Application 60/750,597, filed Dec. 15,        2005;    -   U.S. Provisional Patent Application 60/799,688, filed May 11,        2006;    -   U.S. Provisional Patent Application 60/800,845, filed May 17,        2006, entitled, “Radioimaging camera for dynamic studies”;    -   U.S. Provisional Patent Application 60/800,846, filed May 17,        2006, entitled, “Radioimaging protocols”;    -   U.S. Provisional Patent Application 60/763,458, filed Jan. 31,        2006;    -   U.S. Provisional Patent Application 60/741,440, filed Dec. 2,        2005;    -   U.S. patent application Ser. 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The scope of the present invention includes embodiments described in thearticles and patent publications cited in the Background of theInvention of this application. In an embodiment, techniques andapparatus described in one or more of such references are combined withtechniques and apparatus described herein.

All doses and dose ranges given in this application are for a typicaladult human having a typical body mass of between about 50 and about 90kg. For imaging children, or underweight or overweight adults, the dosesare adjusted appropriately, as known by those skilled in the art.

Although many embodiments of the present invention have been describedas being performed on a cardiac region of interest (ROI), it is to beunderstand that for some applications, the techniques of theseembodiments are used to image a non-cardiac ROI, or both a cardiac ROIand a non-cardiac ROI simultaneously.

It will be appreciated by persons skilled in the art that the presentinvention is not limited to what has been particularly shown anddescribed hereinabove. Rather, the scope of the present inventionincludes both combinations and subcombinations of the various featuresdescribed hereinabove, as well as variations and modifications thereofthat are not in the prior art, which would occur to persons skilled inthe art upon reading the foregoing description.

The invention claimed is:
 1. A method for cardiac imaging, comprising:administering to an adult human subject an amount of a^(99m)Tc-containing species having a radioactivity of less than 5 mCi ata time of administration; and performing a SPECT imaging procedure of acardiac region of interest (ROI) of the subject, wherein said^(99m)Tc-containing species has the formula ^(99m)TcX(Y)₃Z, wherein: Xis an anion; each Y, which is independently chosen, is a vicinal dioximehaving the formula HON═C(R₁)C(R₂)═NOH or a pharmaceutically acceptablesalt thereof, wherein R₁ and R₂ are each independently hydrogen,halogen, alkyl, aryl, amino or a 5 or 6-membered nitrogen or oxygencontaining heterocycle, or together R₁ and R₂ are —(CR₈CR₉)_(n)— whereinn is 3, 4, 5 or 6 and R₈ and R₉ are each independently hydrogen oralkyl; and Z is a boron derivative of the formula B—R₃ wherein R₃ ishydroxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, carboxyalkyl,carboxyalkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl,alkoxyalkenyl, haloalkyl, haloalkenyl, aryl, arylalkyl or (R₄R₅N)-alkyland R₄ and R₅ are each independently hydrogen, alkyl, or arylalkyl, orR₄ and R₅ when taken together with the nitrogen atom to which they areattached form a 5 or 6-membered nitrogen containing heterocycle.
 2. Themethod according to claim 1, wherein said Tc-99m-containing species hasthe structure:


3. The method according to claim 1, comprising mixing: (i) a source ofanion; (ii) a boronic acid derivative, or compounds which can react insitu to form a boronic acid derivative, having the formula R₃B(OR₇)(OR₇)or a pharmaceutically acceptable salt thereof; wherein R₃ is hydroxy,alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, carboxyalkyl,carboxyalkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl,alkoxy-alkenyl, haloalkyl, haloalkenyl, aryl, arylalkyl, or R₄R₅N-alkyland R₄ and R₅ are each independently hydrogen, alkyl, or arylalkyl, orR₄ and R₅ when taken together with nitrogen atom to which they areattached form a 5 or 6-membered nitrogen containing heterocycle, andeach R₇ is independently selected from hydrogen, alkyl and aryl; (iii)at least one dioxime having the formula HON═C(R₁)C(R₂)═NOH or apharmaceutically acceptable salt thereof, wherein R₁ and R₂ are eachindependently hydrogen, halogen, alkyl, aryl, amino or a 5 or 6-memberednitrogen or oxygen containing heterocycle, or together R₁ and R₂ are—(CR₈R₉)_(n)— wherein n is 3, 4, 5 or 6 and R₈ and R₉ are eachindependently hydrogen or alkyl; (iv) a reducing agent; and (v) a sourceof ^(99m)Tc; whereby to obtain the ^(99m)Tc-containing species, whereinadministering comprises administering the ^(99m)Tc-containing speciesthus obtained.
 4. The method according to claim 3, wherein said mixingfurther comprises mixing hydroxypropyl gamma cyclodextrin with saidsource of anion, said boronic acid derivative, said dioxime and saidreducing agent.
 5. The method according to claim 1, wherein performingthe SPECT imaging procedure comprises performing a dynamic SPECT imagingprocedure.
 6. The method according to claim 1, wherein performing theSPECT imaging procedure comprises acquiring at least one in 5000 photonsemitted from the ROI during the SPECT imaging procedure.
 7. The methodaccording to claim 6 , wherein performing, the SPECT imaging procedurecomprises acquiring at least one in 2000 photons emitted from the ROIduring the SPECT imaging procedure.
 8. The method according to claim 1,wherein performing the SPECT imaging procedure comprises performing theSPECT imaging procedure with frames having a duration of no more than 30seconds.
 9. The method according to claim 1, wherein acquiring the imagecomprises acquiring, during the image acquisition period, at least200,000 photons emitted from a portion of the ROI, which portion has avolume of no more than 500 cc.
 10. The method according to claim 9,wherein the portion of the ROI has a volume of no more than 200 cc, andwherein acquiring the image comprises acquiring at least 1,000,000photons during the image acquisition period from the portion of the ROIhaving the volume of no more than 200 cc.
 11. The method according toclaim 1, wherein performing the SPECT imaging procedure comprisesgenerating an image having a resolution of at least 7×7×7 mm.
 12. Themethod according to claim 11, wherein the ^(99m)Tc-containing species asdistributed within the ROI has a range of emission-intensities R, whichis measured as emitted photons/unit time/volume, wherein generating theimage comprises generating a reconstructed three-dimensionalemission-intensity image of the ROI, and wherein at least 50% of voxelsof the image have inaccuracies of less than 30% of range R.
 13. Themethod according to claim 1, wherein the radioactivity is less than orequal to 4 mCi, and wherein administering comprises administering the^(99m)Tc-containing species having the radioactivity less than or equalto 4 mCi.
 14. The method according to claim 1, wherein administeringcomprises administering the ^(99m)Tc-containing species while thesubject is at rest, and wherein performing the SPECT imaging procedurecomprises performing a SPECT rest imaging procedure, and comprising,before or after the administering while the subject is at rest:subjecting the subject to stress; during the stress, administering tothe subject a ^(99m)Tc-containing species having the formula^(99m)TcX(Y)₃Z; and performing a SPECT stress imaging procedure on thesubject.
 15. The method according to claim 1, wherein performing theSPECT imaging procedure of the cardiac ROI comprises performingmyocardial perfusion imaging.
 16. Apparatus for performing cardiacimaging, comprising an imaging system, which comprises: SPECT imagingfunctionality; and a control unit configured to drive the imagingfunctionality to perform a SPECT imaging procedure on a cardiac regionof interest (ROI) of an adult human subject after administration to thesubject of a ^(99m)Tc-containing species having a radioactivity of lessthan 5 mCi at a time of administration, wherein said ^(99m)Tc-containingspecies has the formula ^(99m)TcX(Y)₃Z, wherein: X is an anion; each Y,which is independently chosen, is a vicinal dioxime having the formulaHON═C(R₁)(R₂)═NOH or a pharmaceutically acceptable salt thereof, whereinR₁ and R₂ are each independently hydrogen, halogen, alkyl, aryl, aminoor a 5 or 6-membered, nitrogen or oxygen containing heterocycle, ortogether R₁ and R₂ are —(CR₈CR₉)_(n)— wherein n is 3, 4, 5 or 6 and R₈and R₉ are each independently hydrogen or alkyl; and Z is a boronderivative of the formula B—R₃ wherein R₃ is hydroxy, alkyl, alkenyl,cycloalkyl, cycloalkenyl, alkoxy, carboxyalkyl, carhoxyalkenyl,hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, alkoxyalkenyl, haloalkyl,haloalkenyl, aryl, arylalkyl or (R₄R₅N)-alkyl and R₄ and R₅ are eachindependently hydrogen, alkyl, or arylalkyl, or R₄ and R₅ when takentogether with the nitrogen atom to which they are attached form a 5 or6-membered nitrogen containing heterocycle, wherein the SPECT imagingfunctionality is configured to generate an image having a resolution ofat least 7×7×7 mm.
 17. The apparatus according to claim 16, furthercomprising an automated administration system, configured to receiveimaging protocol information for use with the ^(99m)Tc-containingspecies, and to perform at least one automated administration of the^(99m)Tc-containing species into the subject at least in partresponsively to the protocol information.
 18. The apparatus according toclaim 16, comprising a portable computer-communicatable non-transitorydata carrier containing imaging protocol information for use with the^(99m)Tc-containing species.
 19. The apparatus according to claim 18,comprising an automated administration system, configured to receiveimaging protocol information for use with the ^(99m)Tc-containingspecies from the data carrier, and to perform at least one automatedadministration of the ^(99m)Tc-containing species into the subject atleast in part responsively to the protocol information.
 20. Theapparatus according to claim 16, wherein the control unit is configuredto drive the imaging functionality to perform myocardial perfusionimaging.
 21. The apparatus according to claim 16, wherein the^(99m)Tc-containing species as distributed within the ROI has a range ofemission-intensities which is measured as emitted photons/unittime/volume, wherein the SPECT imaging functionality is configured togenerate a reconstructed three-dimensional emission-intensity image ofthe ROI, and wherein at least 50% of voxels of the image haveinaccuracies of less than 30% of range R.
 22. Apparatus for cardiacimaging, comprising a portable computer-communicatable non-transitorydata carrier, which is configured to contain imaging protocolinformation for performing SPECT imaging on an adult human subject, theprotocol information including an indication to administer a^(99m)Tc-containing species of the formula ^(99m)TcX(Y)₃Z, and anindication to perform a SPECT imaging procedure on the subject, whichprocedure includes an image acquisition period having a duration notexceeding 5 minutes, wherein: X is an anion; each Y, which isindependently chosen, is a vicinal dioxime having the formulaHON═C(R₁)C(R₂)═NOH or a pharmaceutically acceptable salt thereof,wherein R₁ and R₂ are each independently hydrogen, halogen, alkyl, aryl,amino or a 5 or 6-membered nitrogen or oxygen containing heterocycle, ortogether R₁ and R₂ are —(CR₈CR₉)_(n)— wherein n is 3, 4, 5 or 6 and R₈and R₉ are each independently hydrogen or alkyl; and Z is a boronderivative of the formula B—R₃ wherein R₃ is hydroxy, alkyl, alkenyl,cycloalkyl, cycloalkenyl, alkoxy, carboxyalkyl, carboxyalkenyl,hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, alkoxyalkenyl, haloalkyl,haloalkenyl, aryl, arylalkyl or (R₄R₅N)-alkyl and R₄ and R₃ are eachindependently hydrogen, alkyl, or arylalkyl, or R₄ and R₅ when takentogether with the nitrogen atom to which they are attached form a 5 or6-membered nitrogen containing heterocycle.
 23. The apparatus accordingto claim 22, wherein the protocol information includes an indication toperform a SPECT imaging procedure on the subject, which procedureincludes: (a) a duration of an image acquisition period, and (b) aradioactivity of the ^(99m)Tc-containing species, wherein a product (a)and (h) is less than 50 mCi*minutes.
 24. The apparatus according toclaim 22, comprising a container containing the ^(99m)Tc-containingspecies, wherein the data carrier is associated with the container. 25.The apparatus according to claim 22, wherein the data carrier isconfigured to contain imaging protocol information for performingmyocardial perfusion imaging.
 26. A method for cardiac imaging,comprising: administering to an adult human subject a^(99m)Tc-containing species having a radioactivity of less than 50 mCiat a time of the administering; and performing a SPECT imaging procedureon a cardiac region of interest (ROI) of the subject with a imageacquisition period having a duration not exceeding 5 minutes, whereinsaid ^(99m)Tc-containing species has the formula ^(99m)TcX(Y)₃Z,wherein: X is an anion; each Y, which is independently chosen, is avicinal dioxime having the formula HON═C(R₁)C(R₂)═NOH or apharmaceutically acceptable salt thereof, wherein R₁ and R₂ are eachindependently hydrogen, halogen, alkyl, aryl, amino or a 5 or 6-memberednitrogen or oxygen containing heterocycle, or together R₁ and R₂ are—(CR₈CR₉)_(n)— wherein n is 3, 4, 5 or 6 and R₈ and R₉ are eachindependently hydrogen or alkyl; and Z is a boron derivative of theformula B—R₃ wherein R₃ is hydroxy, alkyl, alkenyl, cycloalkyl,cycloalkenyl, alkoxy, carboxyalkyl, carboxyalkenyl, hydroxyalkyl,hydroxyalkenyl, alkoxyalkyl, alkoxyalkenyl, haloalkyl, haloalkenyl,aryl, arylalkyl or (R₄R₅N)-alkyl and R₄ and R₅ are each independentlyhydrogen, alkyl, or arylalkyl, or R₄ and R₅ when taken together with thenitrogen atom to which they are attached form a 5 or 6-membered nitrogencontaining heterocycle.
 27. The method according to claim 26, whereinthe radioactivity is less than 30 mCi.
 28. The method according to claim26, wherein the radioactivity is less than 5 mCi.
 29. The methodaccording to claim 26, wherein the duration of the image acquisitionperiod does not exceed 3 minutes.
 30. The method according to claim 26,wherein performing the SPECT imaging procedure comprises, during theimage acquisition period, acquiring a number of photons emitted from the^(99m)Tc-containing species which is greater than or equal to at leastone of the following numbers: one in 5000 photons emitted by the^(99m)Tc-containing species in the ROI during the image acquisitionperiod, and 200,000 photons emitted by the ^(99m)Tc-containing speciesin a portion of the ROI, which portion has a volume of no more than 500cc.
 31. The method according to claim 30, wherein acquiring the numberof photons comprises acquiring at least one in 5000 photons emitted fromthe ROI during the image acquisition period.
 32. The method according toclaim 30, wherein the portion of the ROI has a volume of no more than200 cc, and wherein acquiring the number of photons comprises acquiringat least 1,000,000 photons during the image acquisition period from theportion of the ROI having the volume of no more than 200 cc.
 33. Themethod according to claim 26, wherein performing the SPECT imagingprocedure comprises generating an image having a resolution of at least7×7×7 mm.
 34. The method according to claim 33, wherein the^(99m)Tc-containing species as distributed within the ROI has a range ofemission-intensities R, which is measured as emitted photons/unittime/volume, wherein performing the SPECT imaging procedure generating areconstructed three-dimensional emission-intensity image of the ROI, andwherein at least 50% of voxels of the image have inaccuracies of lessthan 30% of range R.
 35. The method according to claim 26, whereinadministering comprises administering the ^(99m)Tc-containing specieswhile the subject is at rest, wherein performing the SPECT imagingprocedure comprises performing a SPECT rest imaging procedure, andcomprising, after completion of the SPECT rest imaging procedure:subjecting the subject to stress; during the stress, administering intothe subject the ^(99m)Tc-containing species having a radioactivity ofbetween 15 and 40 mCi at a time of the administering; and performing aSPECT stress imaging procedure on the subject.
 36. The method accordingto claim 26, wherein administering comprises administering the^(99m)Tc-containing species while the subject is at rest, whereinperforming the SPECT imaging procedure comprises performing a SPECT restimaging procedure, and comprising, after completion of the SPECT restimaging procedure: subjecting the subject to stress; during the stress,administering to the subject thallium having a radioactivity of between3 and 5 mCi at a time of the administering; and performing SPECT stressimaging on the subject.
 37. The method according to claim 26, whereinadministering comprises administering the ^(99m)Tc-containing specieswhile the subject is at rest, wherein performing the SPECT imagingprocedure comprises performing a SPECT rest imaging procedure, andcomprising, before administering the ^(99m)Tc-containing species whilethe subject is at rest: subjecting the subject to stress; during thestress, administering to the subject thallium having a radioactivity ofbetween 3 and 5 mCi at a time of the administering; and performing SPECTstress imaging on the subject.
 38. The method according to claim 26,wherein administering comprises administering the ^(99m)Tc-containingspecies while the subject is at rest, wherein performing the SPECTimaging procedure comprises performing a SPECT rest imaging procedure,and comprising: before administering the ^(99m)Tc-containing specieswhile the subject is at rest: subjecting the subject to stress; andduring the stress, administering to the subject thallium having aradioactivity of between 3 and 5 mCi at a time of the administering; andbefore performing the SPECT rest imaging procedure, performing SPECTstress imaging on the subject.
 39. The method according to claim 26,wherein administering comprises administering the ^(99m)Tc-containingspecies while the subject is at rest, wherein performing the SPECTimaging procedure comprises performing a SPECT rest imaging procedure,and comprising: before administering the ^(99m)Tc-containing specieswhile the subject is at rest: subjecting the subject to stress; andduring the stress, administering to the subject thallium having aradioactivity of between 3 and 5 mCi at a time of the administering; andperforming SPECT stress imaging on the subject simultaneously withperforming the SPECT rest imaging procedure.
 40. The method according toclaim 26, wherein administering comprises subjecting the subject tostress, and administering the ^(99m)Tc-containing species during thestress, wherein performing the SPECT imaging procedure comprisesperforming a SPECT stress imaging procedure of the ^(99m)Tc-containingspecies, and comprising: after administering the ^(99m)Tc-containingspecies, administering to the subject, while the subject is at rest,thallium having a radioactivity of between 3 and 5 mCi at a time of theadministering; and after performing the SPECT stress imaging procedure,performing a SPECT rest imaging procedure of the thallium.
 41. Themethod according to claim 26, wherein administering comprises subjectingthe subject to stress, and administering the ^(99m)Tc-containing speciesduring the stress, wherein performing the SPECT imaging procedurecomprises performing a SPECT stress imaging procedure of the^(99m)Tc-containing species, and comprising: before administering the^(99m)Tc-containing species, administering to the subject, while thesubject is at rest, thallium having a radioactivity of between 3 and 5mCi at a time of the administering; and performing a SPECT rest imagingprocedure of the thallium, after performing the SPECT stress imagingprocedure of the ^(99m)Tc-containing species.
 42. The method accordingto claim 26, wherein administering comprises subjecting the subject tostress, and administering the ^(99m)Tc-containing species during thestress, wherein performing the SPECT imaging procedure comprisesperforming a SPECT stress imaging procedure of the ^(99m)Tc-containingspecies, and comprising: before administering the ^(99m)Tc-containingspecies, administering to the subject, while the subject is at rest,thallium having a radioactivity of between 3 and 5 mCi at a time of theadministering; and performing a SPECT rest imaging of the thalliumsimultaneously with performing the SPECT stress imaging procedure of the^(99m)Tc-containing species.
 43. The method according to claim 42,wherein administering the ^(99m)Tc-containing species and administeringthe thallium comprise administering the ^(99m)Tc-containing species andthe thallium using an automated administration system that is configuredto receive imaging protocol information for use with the^(99m)Tc-containing species and the thallium, and to administer the^(99m)Tc-containing species and the thallium into the subject at leastin part responsively to the protocol information.
 44. The methodaccording to claim 26, wherein performing the SPECT imaging procedurecomprises performing a SPECT rest imaging procedure, and wherein themethod further comprises: administering to the subject aradiopharmaceutical agent different from the ^(99m)Tc-containingspecies; and performing a SPECT stress imaging procedure on the ROI,wherein administering the ^(99m)Tc-containing species, performing theSPECT rest imaging procedure, and performing the SPECT stress imagingprocedure comprise administering the ^(99m)Tc-containing species,performing the SPECT rest imaging procedure, and performing the SPECTstress imaging procedure while the subject remains in place at a cameraof an imaging system.
 45. The method according to claim 26, comprising,prior to or during performance of the SPECT imaging procedure,administering to the subject I-123 BMIPP, wherein performing the SPECTimaging procedure comprises simultaneously imaging the^(99m)Tc-containing species and the I-123 BMIPP.
 46. The methodaccording to claim 26, wherein performing the SPECT imaging procedurecomprises performing a first SPECT imaging procedure, and comprising,after completion of the first SPECT imaging procedure: administering tothe subject at least one additional ^(99m)Tc-containing speciesdifferent from the ^(99m)Tc-containing species having the formula^(99m)TcX(Y)₃Z; and performing a second SPECT imaging procedure usingthe at least one additional ^(99m)Tc-containing species.
 47. The methodaccording to claim 46, wherein the at least one additional^(99m)Tc-containing species comprises ^(99m)Tc-sestamibi.
 48. The methodaccording to claim 46, wherein the at least one additional^(99m)Tc-containing species comprises ^(99m)Tc-tetrofosmin.
 49. Themethod according to claim 26, wherein performing the SPECT imagingprocedure comprises completing image acquisition less than 6 minutesafter completing the administering of the ^(99m)Tc-containing species.50. The method according to claim 26, wherein performing the SPECTimaging procedure of the cardiac ROI comprises performing myocardialperfusion imaging.
 51. Apparatus for performing cardiac imaging,comprising an imaging system, which comprises: SPECT imagingfunctionality; and a control unit configured to drive, the imagingfunctionality to perform a SPECT imaging procedure on a cardiac regionof interest (ROD of an adult human subject after administration to thesubject of a ^(99m)Tc-containing species having a radioactivity of lessthan 50 mCi at a time of the administration, wherein the imagingprocedure has a image acquisition period having a duration not exceeding5 minutes, and wherein said ^(99m)Tc-containing species has the formula^(99m)TcX(Y)₃Z, wherein: X is an anion; each Y, which is independentlychosen, is a vicinal dioxime having the formula HON═C(R₁)C(R₂)═NOH or apharmaceutically acceptable salt thereof, wherein R₁ and R₂ are eachindependently hydrogen, halogen, alkyl, aryl, amino or a 5 or 6-memberednitrogen or oxygen containing heterocycle, or together R₁ and R₂ are—(CR₈CR₉)_(n)— wherein n is 3, 4, 5 or 6 and R₈ and R₉ are eachindependently hydrogen or alkyl; and Z is a boron derivative of theformula B—R₃ wherein R₃ is hydroxy, alkyl, alkenyl, cycloalkyl,cycloalkenyl, alkoxy, carboxyalkyl, carboxyalkenyl, hydroxyalkyl,hydroxyalkenyl, alkoxyalkyl, alkoxyalkenyl, haloalkyl, haloalkenyl,aryl, arylalkyl or (R₄R₅N)-alkyl and R₄ and R₅ are each independentlyhydrogen, alkyl, or arylalkyl, or R₄ and R₅ when taken together with thenitrogen atom to which they are attached form a 5 or 6-membered nitrogencontaining heterocycle, wherein the SPECT imaging functionality isconfigured to generate an image having a resolution of at least 7×7×7mm.
 52. The apparatus according to claim 51, wherein the radioactivityis less than 30 mCi.
 53. The apparatus according to claim 51, comprisinga portable computer-communicatable non-transitory data carriercontaining imaging protocol information for use with the^(99m)Tc-containing species.
 54. The apparatus according to claim 51,comprising an automated administration system, configured to receiveimaging protocol information for use with the ^(99m)Tc-containingspecies, and to perform at least one automated administration of the^(99m)Tc-containing species into the subject at least in partresponsively to the protocol information.
 55. The apparatus according toclaim 51, wherein the control unit is configured to drive the imagingfunctionality to perform myocardial perfusion imaging.
 56. The apparatusaccording to claim 51, wherein the ^(99m)Tc-containing species asdistributed within the ROI has a range of emission-intensities R, whichis measured as emitted photons/unit time/volume, wherein the SPECTimaging functionality is configured to generate a reconstructedthree-dimensional emission-intensity image of the ROI, and wherein atleast 50% of voxels of the image have inaccuracies of less than 30% ofrange R.
 57. A method for cardiac imaging, comprising: subjecting anadult human subject to stress; during the stress, administering to thesubject a ^(99m)Tc-containing species having a radioactivity of between20 and 40 mCi at a time of the administering; and performing a SPECTstress imaging procedure on a cardiac region of interest (ROI) of thesubject, with an image acquisition period having a duration notexceeding 5 minutes; and during the stress image acquisition period,acquiring a number of photons greater than or equal to at least one ofthe following numbers: one in 5000 photons emitted from the ROI duringthe stress image acquisition period, and 200,000 photons emitted from aportion of the ROI, which portion has a volume of no more than 500 cc,wherein said ^(99m)Tc-containing species has the formula ^(99m)TcX(Y)₃Z,wherein: X is an anion; each Y, which is independently chosen, is avicinal dioxime having the formula HON═C(R₁)C(R₂)═NOH or apharmaceutically acceptable salt thereof, wherein R₁ and R₂ are eachindependently hydrogen, halogen, alkyl, aryl, amino or a 5 or 6-memberednitrogen or oxygen containing heterocycle, or together R₁ and R₂ are—(CR₈CR₉)_(n)— wherein n is 3, 4, 5 or 6 and R₅ and R₉ are eachindependently hydrogen or alkyl; and Z is a boron derivative of theformula B—R₃ wherein R₃ is hydroxy, alkyl, alkenyl, cycloalkyl,cycloalkenyl, alkoxy, carboxyalkyl, carboxyalkenyl, hydroxyalkyl,hydroxyalkenyl, alkoxyalkyl, alkoxyalkenyl, haloalkyl, haloalkenyl,aryl, arylalkyl or (R₄R₅N)-alkyl and R₄ and R₅ are each independentlyhydrogen, alkyl, or arylalkyl, or R₄ and R₅ when taken together with thenitrogen atom to which they are attached form a 5 or 6-membered nitrogencontaining heterocycle.
 58. The method according to claim 57,comprising, prior to subjecting the subject to the stress:administering, while the subject is at rest, thallium to the subjecthaving a radioactivity of between 2 and 5 mCi at a time of theadministering; and performing SPECT rest imaging on the subject.
 59. Themethod according to claim 57, wherein performing the SPECT stressimaging procedure of the cardiac ROI comprises performing myocardialperfusion imaging.